Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
Identifieur interne : 000B44 ( Pmc/Corpus ); précédent : 000B43; suivant : 000B45Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
Auteurs : Timothy R. Rebbeck ; Tara M. Friebel ; Nandita Mitra ; Fei Wan ; Stephanie Chen ; Irene L. Andrulis ; Paraskevi Apostolou ; Norbert Arnold ; Banu K. Arun ; Daniel Barrowdale ; Javier Benitez ; Raanan Berger ; Pascaline Berthet ; Ake Borg ; Saundra S. Buys ; Trinidad Caldes ; Jonathan Carter ; Jocelyne Chiquette ; Kathleen B. M. Claes ; Fergus J. Couch ; Cezary Cybulski ; Mary B. Daly ; Miguel De La Hoya ; Orland Diez ; Susan M. Domchek ; Katherine L. Nathanson ; Katarzyna Durda ; Steve Ellis ; D. Gareth Evans ; Lenka Foretova ; Eitan Friedman ; Debra Frost ; Patricia A. Ganz ; Judy Garber ; Gord Glendon ; Andrew K. Godwin ; Mark H. Greene ; Jacek Gronwald ; Eric Hahnen ; Emily Hallberg ; Ute Hamann ; Thomas V. O. Hansen ; Evgeny N. Imyanitov ; Claudine Isaacs ; Anna Jakubowska ; Ramunas Janavicius ; Katarzyna Jaworska-Bieniek ; Esther M. John ; Beth Y. Karlan ; Bella Kaufman ; Kconfab Investigators ; Ava Kwong ; Yael Laitman ; Christine Lasset ; Conxi Lazaro ; Jenny Lester ; Niklas Loman ; Jan Lubinski ; Siranoush Manoukian ; Gillian Mitchell ; Marco Montagna ; Susan L. Neuhausen ; Heli Nevanlinna ; Dieter Niederacher ; Robert L. Nussbaum ; Kenneth Offit ; Edith Olah ; Olufunmilayo I. Olopade ; Sue Kyung Park ; Marion Piedmonte ; Paolo Radice ; Christine Rappaport-Fuerhauser ; Matti A. Rookus ; Caroline Seynaeve ; Jacques Simard ; Christian F. Singer ; Penny Soucy ; Melissa Southey ; Dominique Stoppa-Lyonnet ; Grzegorz Sukiennicki ; Csilla I. Szabo ; Mariella Tancredi ; Manuel R. Teixeira ; Soo-Hwang Teo ; Mary Beth Terry ; Mads Thomassen ; Laima Tihomirova ; Marc Tischkowitz ; Amanda Ewart Toland ; Aleksandra Toloczko-Grabarek ; Nadine Tung ; Elizabeth J. Van Rensburg ; Danylo Villano ; Shan Wang-Gohrke ; Barbara Wappenschmidt ; Jeffrey N. Weitzel ; Jamal Zidan ; Kristin K. Zorn ; Lesley Mcguffog ; Douglas Easton ; Georgia Chenevix-Trench ; Antonis C. Antoniou ; Susan J. RamusSource :
- Breast Cancer Research : BCR [ 1465-5411 ] ; 2016.
Abstract
Most
From 32,295 female
The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC;
Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
The online version of this article (doi:10.1186/s13058-016-0768-3) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s13058-016-0768-3
PubMed: 27836010
PubMed Central: 5106833
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PMC:5106833Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Inheritance of deleterious mutations at both <italic>BRCA1</italic> and <italic>BRCA2</italic> in an international sample of 32,295 women</title><author><name sortKey="Rebbeck, Timothy R" sort="Rebbeck, Timothy R" uniqKey="Rebbeck T" first="Timothy R." last="Rebbeck">Timothy R. Rebbeck</name><affiliation><nlm:aff id="Aff1">Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</nlm:aff></affiliation></author><author><name sortKey="Friebel, Tara M" sort="Friebel, Tara M" uniqKey="Friebel T" first="Tara M." last="Friebel">Tara M. Friebel</name><affiliation><nlm:aff id="Aff1">Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</nlm:aff></affiliation></author><author><name sortKey="Mitra, Nandita" sort="Mitra, Nandita" uniqKey="Mitra N" first="Nandita" last="Mitra">Nandita Mitra</name><affiliation><nlm:aff id="Aff2">Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</nlm:aff></affiliation></author><author><name sortKey="Wan, Fei" sort="Wan, Fei" uniqKey="Wan F" first="Fei" last="Wan">Fei Wan</name><affiliation><nlm:aff id="Aff3">Biostatistics Unit, Group Health Research Institute, Seattle, WA USA</nlm:aff></affiliation></author><author><name sortKey="Chen, Stephanie" sort="Chen, Stephanie" uniqKey="Chen S" first="Stephanie" last="Chen">Stephanie Chen</name><affiliation><nlm:aff id="Aff4">Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA</nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="Aff7">Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8">Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario Canada</nlm:aff></affiliation></author><author><name sortKey="Apostolou, Paraskevi" sort="Apostolou, Paraskevi" uniqKey="Apostolou P" first="Paraskevi" last="Apostolou">Paraskevi Apostolou</name><affiliation><nlm:aff id="Aff9">Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research “Demokritos”, Patriarchou Gregoriou & Neapoleos str. Aghia Paraskevi Attikis, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Arnold, Norbert" sort="Arnold, Norbert" uniqKey="Arnold N" first="Norbert" last="Arnold">Norbert Arnold</name><affiliation><nlm:aff id="Aff10">Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Arun, Banu K" sort="Arun, Banu K" uniqKey="Arun B" first="Banu K." last="Arun">Banu K. Arun</name><affiliation><nlm:aff id="Aff11">Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX USA</nlm:aff></affiliation></author><author><name sortKey="Barrowdale, Daniel" sort="Barrowdale, Daniel" uniqKey="Barrowdale D" first="Daniel" last="Barrowdale">Daniel Barrowdale</name><affiliation><nlm:aff id="Aff5">Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benitez">Javier Benitez</name><affiliation><nlm:aff id="Aff12">Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="Aff13">Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14">Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Berger, Raanan" sort="Berger, Raanan" uniqKey="Berger R" first="Raanan" last="Berger">Raanan Berger</name><affiliation><nlm:aff id="Aff15">The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation></author><author><name sortKey="Berthet, Pascaline" sort="Berthet, Pascaline" uniqKey="Berthet P" first="Pascaline" last="Berthet">Pascaline Berthet</name><affiliation><nlm:aff id="Aff16">Centre François Baclesse, 3 avenue Général Harris, Caen, France</nlm:aff></affiliation></author><author><name sortKey="Borg, Ake" sort="Borg, Ake" uniqKey="Borg A" first="Ake" last="Borg">Ake Borg</name><affiliation><nlm:aff id="Aff17">Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Buys, Saundra S" sort="Buys, Saundra S" uniqKey="Buys S" first="Saundra S." last="Buys">Saundra S. Buys</name><affiliation><nlm:aff id="Aff18">Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112 USA</nlm:aff></affiliation></author><author><name sortKey="Caldes, Trinidad" sort="Caldes, Trinidad" uniqKey="Caldes T" first="Trinidad" last="Caldes">Trinidad Caldes</name><affiliation><nlm:aff id="Aff19">Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Carter, Jonathan" sort="Carter, Jonathan" uniqKey="Carter J" first="Jonathan" last="Carter">Jonathan Carter</name><affiliation><nlm:aff id="Aff20">Gynaecological Oncology, The University of Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Chiquette, Jocelyne" sort="Chiquette, Jocelyne" uniqKey="Chiquette J" first="Jocelyne" last="Chiquette">Jocelyne Chiquette</name><affiliation><nlm:aff id="Aff21">Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050 chemin Sainte-Foy, Québec Canada</nlm:aff></affiliation></author><author><name sortKey="Claes, Kathleen B M" sort="Claes, Kathleen B M" uniqKey="Claes K" first="Kathleen B. M." last="Claes">Kathleen B. M. Claes</name><affiliation><nlm:aff id="Aff22">Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000 Gent, Belgium</nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="Aff23">Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota USA</nlm:aff></affiliation></author><author><name sortKey="Cybulski, Cezary" sort="Cybulski, Cezary" uniqKey="Cybulski C" first="Cezary" last="Cybulski">Cezary Cybulski</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Daly, Mary B" sort="Daly, Mary B" uniqKey="Daly M" first="Mary B." last="Daly">Mary B. Daly</name><affiliation><nlm:aff id="Aff25">Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 USA</nlm:aff></affiliation></author><author><name sortKey="De La Hoya, Miguel" sort="De La Hoya, Miguel" uniqKey="De La Hoya M" first="Miguel" last="De La Hoya">Miguel De La Hoya</name><affiliation><nlm:aff id="Aff19">Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Diez, Orland" sort="Diez, Orland" uniqKey="Diez O" first="Orland" last="Diez">Orland Diez</name><affiliation><nlm:aff id="Aff26">Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Domchek, Susan M" sort="Domchek, Susan M" uniqKey="Domchek S" first="Susan M." last="Domchek">Susan M. Domchek</name><affiliation><nlm:aff id="Aff27">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</nlm:aff></affiliation></author><author><name sortKey="Nathanson, Katherine L" sort="Nathanson, Katherine L" uniqKey="Nathanson K" first="Katherine L." last="Nathanson">Katherine L. Nathanson</name><affiliation><nlm:aff id="Aff27">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</nlm:aff></affiliation></author><author><name sortKey="Durda, Katarzyna" sort="Durda, Katarzyna" uniqKey="Durda K" first="Katarzyna" last="Durda">Katarzyna Durda</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Ellis, Steve" sort="Ellis, Steve" uniqKey="Ellis S" first="Steve" last="Ellis">Steve Ellis</name><affiliation><nlm:aff id="Aff28">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Evans, D Gareth" sort="Evans, D Gareth" uniqKey="Evans D" first="D. Gareth" last="Evans">D. Gareth Evans</name><affiliation><nlm:aff id="Aff29">Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Foretova, Lenka" sort="Foretova, Lenka" uniqKey="Foretova L" first="Lenka" last="Foretova">Lenka Foretova</name><affiliation><nlm:aff id="Aff30">Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653 Czech Republic</nlm:aff></affiliation></author><author><name sortKey="Friedman, Eitan" sort="Friedman, Eitan" uniqKey="Friedman E" first="Eitan" last="Friedman">Eitan Friedman</name><affiliation><nlm:aff id="Aff31">The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff32">Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel</nlm:aff></affiliation></author><author><name sortKey="Frost, Debra" sort="Frost, Debra" uniqKey="Frost D" first="Debra" last="Frost">Debra Frost</name><affiliation><nlm:aff id="Aff28">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Ganz, Patricia A" sort="Ganz, Patricia A" uniqKey="Ganz P" first="Patricia A." last="Ganz">Patricia A. Ganz</name><affiliation><nlm:aff id="Aff33">UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA 90095-6900 USA</nlm:aff></affiliation></author><author><name sortKey="Garber, Judy" sort="Garber, Judy" uniqKey="Garber J" first="Judy" last="Garber">Judy Garber</name><affiliation><nlm:aff id="Aff1">Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</nlm:aff></affiliation></author><author><name sortKey="Glendon, Gord" sort="Glendon, Gord" uniqKey="Glendon G" first="Gord" last="Glendon">Gord Glendon</name><affiliation><nlm:aff id="Aff34">Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada</nlm:aff></affiliation></author><author><name sortKey="Godwin, Andrew K" sort="Godwin, Andrew K" uniqKey="Godwin A" first="Andrew K." last="Godwin">Andrew K. Godwin</name><affiliation><nlm:aff id="Aff35">Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS 3040 Kansas, USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff36">University of Kansas Medical Center, Kansas City, Kansas USA</nlm:aff></affiliation></author><author><name sortKey="Greene, Mark H" sort="Greene, Mark H" uniqKey="Greene M" first="Mark H." last="Greene">Mark H. Greene</name><affiliation><nlm:aff id="Aff37">Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD USA</nlm:aff></affiliation></author><author><name sortKey="Gronwald, Jacek" sort="Gronwald, Jacek" uniqKey="Gronwald J" first="Jacek" last="Gronwald">Jacek Gronwald</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Hahnen, Eric" sort="Hahnen, Eric" uniqKey="Hahnen E" first="Eric" last="Hahnen">Eric Hahnen</name><affiliation><nlm:aff id="Aff38">Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Hallberg, Emily" sort="Hallberg, Emily" uniqKey="Hallberg E" first="Emily" last="Hallberg">Emily Hallberg</name><affiliation><nlm:aff id="Aff39">Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ USA</nlm:aff></affiliation></author><author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name><affiliation><nlm:aff id="Aff40">Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Hansen, Thomas V O" sort="Hansen, Thomas V O" uniqKey="Hansen T" first="Thomas V. O." last="Hansen">Thomas V. O. Hansen</name><affiliation><nlm:aff id="Aff41">Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Imyanitov, Evgeny N" sort="Imyanitov, Evgeny N" uniqKey="Imyanitov E" first="Evgeny N." last="Imyanitov">Evgeny N. Imyanitov</name><affiliation><nlm:aff id="Aff43">N.N. Petrov Institute of Oncology, St.-Petersburg, 197758 Russia</nlm:aff></affiliation></author><author><name sortKey="Isaacs, Claudine" sort="Isaacs, Claudine" uniqKey="Isaacs C" first="Claudine" last="Isaacs">Claudine Isaacs</name><affiliation><nlm:aff id="Aff44">Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC USA</nlm:aff></affiliation></author><author><name sortKey="Jakubowska, Anna" sort="Jakubowska, Anna" uniqKey="Jakubowska A" first="Anna" last="Jakubowska">Anna Jakubowska</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Janavicius, Ramunas" sort="Janavicius, Ramunas" uniqKey="Janavicius R" first="Ramunas" last="Janavicius">Ramunas Janavicius</name><affiliation><nlm:aff id="Aff45">Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Santariskiu st, Vilnius, Lithuania</nlm:aff></affiliation><affiliation><nlm:aff id="Aff46">State Research Institute Centre for Innovative medicine, Zygymantu st. 9, Vilnius, Lithuania</nlm:aff></affiliation></author><author><name sortKey="Jaworska Bieniek, Katarzyna" sort="Jaworska Bieniek, Katarzyna" uniqKey="Jaworska Bieniek K" first="Katarzyna" last="Jaworska-Bieniek">Katarzyna Jaworska-Bieniek</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="Aff47">Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538 USA</nlm:aff></affiliation></author><author><name sortKey="Karlan, Beth Y" sort="Karlan, Beth Y" uniqKey="Karlan B" first="Beth Y." last="Karlan">Beth Y. Karlan</name><affiliation><nlm:aff id="Aff48">Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA USA</nlm:aff></affiliation></author><author><name sortKey="Kaufman, Bella" sort="Kaufman, Bella" uniqKey="Kaufman B" first="Bella" last="Kaufman">Bella Kaufman</name><affiliation><nlm:aff id="Aff15">The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation></author><author><name sortKey="Investigators, Kconfab" sort="Investigators, Kconfab" uniqKey="Investigators K" first="Kconfab" last="Investigators">Kconfab Investigators</name><affiliation><nlm:aff id="Aff49">Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Kwong, Ava" sort="Kwong, Ava" uniqKey="Kwong A" first="Ava" last="Kwong">Ava Kwong</name><affiliation><nlm:aff id="Aff50">The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong</nlm:aff></affiliation><affiliation><nlm:aff id="Aff51">Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong</nlm:aff></affiliation></author><author><name sortKey="Laitman, Yael" sort="Laitman, Yael" uniqKey="Laitman Y" first="Yael" last="Laitman">Yael Laitman</name><affiliation><nlm:aff id="Aff31">The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff32">Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel</nlm:aff></affiliation></author><author><name sortKey="Lasset, Christine" sort="Lasset, Christine" uniqKey="Lasset C" first="Christine" last="Lasset">Christine Lasset</name><affiliation><nlm:aff id="Aff52">Unité de Prévention et d’Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Lazaro, Conxi" sort="Lazaro, Conxi" uniqKey="Lazaro C" first="Conxi" last="Lazaro">Conxi Lazaro</name><affiliation><nlm:aff id="Aff53">Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute) Catalan Institute of Oncology, Gran Via de l’Hospitalet, 199-203, 08908, L’Hospitalet Barcelona, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Lester, Jenny" sort="Lester, Jenny" uniqKey="Lester J" first="Jenny" last="Lester">Jenny Lester</name><affiliation><nlm:aff id="Aff48">Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA USA</nlm:aff></affiliation></author><author><name sortKey="Loman, Niklas" sort="Loman, Niklas" uniqKey="Loman N" first="Niklas" last="Loman">Niklas Loman</name><affiliation><nlm:aff id="Aff54">Department of Oncology, Lund University Hospital, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lubinski, Jan" sort="Lubinski, Jan" uniqKey="Lubinski J" first="Jan" last="Lubinski">Jan Lubinski</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Manoukian, Siranoush" sort="Manoukian, Siranoush" uniqKey="Manoukian S" first="Siranoush" last="Manoukian">Siranoush Manoukian</name><affiliation><nlm:aff id="Aff55">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Gillian" sort="Mitchell, Gillian" uniqKey="Mitchell G" first="Gillian" last="Mitchell">Gillian Mitchell</name><affiliation><nlm:aff id="Aff56">Familial Cancer Centre, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006 Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff57">Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052 Australia</nlm:aff></affiliation></author><author><name sortKey="Montagna, Marco" sort="Montagna, Marco" uniqKey="Montagna M" first="Marco" last="Montagna">Marco Montagna</name><affiliation><nlm:aff id="Aff58">Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOC - IRCCS, Via Gattamelata 64, Padua, Italy</nlm:aff></affiliation></author><author><name sortKey="Neuhausen, Susan L" sort="Neuhausen, Susan L" uniqKey="Neuhausen S" first="Susan L." last="Neuhausen">Susan L. Neuhausen</name><affiliation><nlm:aff id="Aff59">Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA USA</nlm:aff></affiliation></author><author><name sortKey="Nevanlinna, Heli" sort="Nevanlinna, Heli" uniqKey="Nevanlinna H" first="Heli" last="Nevanlinna">Heli Nevanlinna</name><affiliation><nlm:aff id="Aff60">Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700, (Haartmaninkatu 8), 00029 HUS Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Niederacher, Dieter" sort="Niederacher, Dieter" uniqKey="Niederacher D" first="Dieter" last="Niederacher">Dieter Niederacher</name><affiliation><nlm:aff id="Aff61">Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany</nlm:aff></affiliation></author><author><name sortKey="Nussbaum, Robert L" sort="Nussbaum, Robert L" uniqKey="Nussbaum R" first="Robert L." last="Nussbaum">Robert L. Nussbaum</name><affiliation><nlm:aff id="Aff62">513 Parnassus Ave., HSE 901E, San Francisco, CA 94143-0794 USA</nlm:aff></affiliation></author><author><name sortKey="Offit, Kenneth" sort="Offit, Kenneth" uniqKey="Offit K" first="Kenneth" last="Offit">Kenneth Offit</name><affiliation><nlm:aff id="Aff63">Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10044 USA</nlm:aff></affiliation></author><author><name sortKey="Olah, Edith" sort="Olah, Edith" uniqKey="Olah E" first="Edith" last="Olah">Edith Olah</name><affiliation><nlm:aff id="Aff64">Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary</nlm:aff></affiliation></author><author><name sortKey="Olopade, Olufunmilayo I" sort="Olopade, Olufunmilayo I" uniqKey="Olopade O" first="Olufunmilayo I." last="Olopade">Olufunmilayo I. Olopade</name><affiliation><nlm:aff id="Aff65">5841 South Maryland Avenue, MC 2115 Chicago, IL USA</nlm:aff></affiliation></author><author><name sortKey="Park, Sue Kyung" sort="Park, Sue Kyung" uniqKey="Park S" first="Sue Kyung" last="Park">Sue Kyung Park</name><affiliation><nlm:aff id="Aff66">Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 Korea</nlm:aff></affiliation></author><author><name sortKey="Piedmonte, Marion" sort="Piedmonte, Marion" uniqKey="Piedmonte M" first="Marion" last="Piedmonte">Marion Piedmonte</name><affiliation><nlm:aff id="Aff67">NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY 14263 USA</nlm:aff></affiliation></author><author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name><affiliation><nlm:aff id="Aff68">Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133 Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Rappaport Fuerhauser, Christine" sort="Rappaport Fuerhauser, Christine" uniqKey="Rappaport Fuerhauser C" first="Christine" last="Rappaport-Fuerhauser">Christine Rappaport-Fuerhauser</name><affiliation><nlm:aff id="Aff69">Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Rookus, Matti A" sort="Rookus, Matti A" uniqKey="Rookus M" first="Matti A." last="Rookus">Matti A. Rookus</name><affiliation><nlm:aff id="Aff70">Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000 BE Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Seynaeve, Caroline" sort="Seynaeve, Caroline" uniqKey="Seynaeve C" first="Caroline" last="Seynaeve">Caroline Seynaeve</name><affiliation><nlm:aff id="Aff71">Department of Medical Oncology, Family Cancer Clinic Erasmus University Medical Center Cancer institute, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name><affiliation><nlm:aff id="Aff72">Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec Canada</nlm:aff></affiliation></author><author><name sortKey="Singer, Christian F" sort="Singer, Christian F" uniqKey="Singer C" first="Christian F." last="Singer">Christian F. Singer</name><affiliation><nlm:aff id="Aff73">Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Soucy, Penny" sort="Soucy, Penny" uniqKey="Soucy P" first="Penny" last="Soucy">Penny Soucy</name><affiliation><nlm:aff id="Aff72">Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec Canada</nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa" sort="Southey, Melissa" uniqKey="Southey M" first="Melissa" last="Southey">Melissa Southey</name><affiliation><nlm:aff id="Aff74">Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria Australia</nlm:aff></affiliation></author><author><name sortKey="Stoppa Lyonnet, Dominique" sort="Stoppa Lyonnet, Dominique" uniqKey="Stoppa Lyonnet D" first="Dominique" last="Stoppa-Lyonnet">Dominique Stoppa-Lyonnet</name><affiliation><nlm:aff id="Aff75">Service de Génétique Oncologique, Institut Curie, 26, rue d’Ulm, Paris, Cedex 05, France</nlm:aff></affiliation></author><author><name sortKey="Sukiennicki, Grzegorz" sort="Sukiennicki, Grzegorz" uniqKey="Sukiennicki G" first="Grzegorz" last="Sukiennicki">Grzegorz Sukiennicki</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Szabo, Csilla I" sort="Szabo, Csilla I" uniqKey="Szabo C" first="Csilla I." last="Szabo">Csilla I. Szabo</name><affiliation><nlm:aff id="Aff76">National Human Genome Research Institute, National Institutes of Health Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD 20892-8004 USA</nlm:aff></affiliation></author><author><name sortKey="Tancredi, Mariella" sort="Tancredi, Mariella" uniqKey="Tancredi M" first="Mariella" last="Tancredi">Mariella Tancredi</name><affiliation><nlm:aff id="Aff77">Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Teixeira, Manuel R" sort="Teixeira, Manuel R" uniqKey="Teixeira M" first="Manuel R." last="Teixeira">Manuel R. Teixeira</name><affiliation><nlm:aff id="Aff78">Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal</nlm:aff></affiliation></author><author><name sortKey="Teo, Soo Hwang" sort="Teo, Soo Hwang" uniqKey="Teo S" first="Soo-Hwang" last="Teo">Soo-Hwang Teo</name><affiliation><nlm:aff id="Aff79">Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Malaysia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff80">University Malaya Cancer Research Institute, University Malaya, 50603 Kuala Lumpur, Malaysia</nlm:aff></affiliation></author><author><name sortKey="Terry, Mary Beth" sort="Terry, Mary Beth" uniqKey="Terry M" first="Mary Beth" last="Terry">Mary Beth Terry</name><affiliation><nlm:aff id="Aff81">Department of Epidemiology, Columbia University, New York, NY USA</nlm:aff></affiliation></author><author><name sortKey="Thomassen, Mads" sort="Thomassen, Mads" uniqKey="Thomassen M" first="Mads" last="Thomassen">Mads Thomassen</name><affiliation><nlm:aff id="Aff82">Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark</nlm:aff></affiliation></author><author><name sortKey="Tihomirova, Laima" sort="Tihomirova, Laima" uniqKey="Tihomirova L" first="Laima" last="Tihomirova">Laima Tihomirova</name><affiliation><nlm:aff id="Aff83">Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia</nlm:aff></affiliation></author><author><name sortKey="Tischkowitz, Marc" sort="Tischkowitz, Marc" uniqKey="Tischkowitz M" first="Marc" last="Tischkowitz">Marc Tischkowitz</name><affiliation><nlm:aff id="Aff84">Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec Canada</nlm:aff></affiliation></author><author><name sortKey="Toland, Amanda Ewart" sort="Toland, Amanda Ewart" uniqKey="Toland A" first="Amanda Ewart" last="Toland">Amanda Ewart Toland</name><affiliation><nlm:aff id="Aff85">Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH USA</nlm:aff></affiliation></author><author><name sortKey="Toloczko Grabarek, Aleksandra" sort="Toloczko Grabarek, Aleksandra" uniqKey="Toloczko Grabarek A" first="Aleksandra" last="Toloczko-Grabarek">Aleksandra Toloczko-Grabarek</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Tung, Nadine" sort="Tung, Nadine" uniqKey="Tung N" first="Nadine" last="Tung">Nadine Tung</name><affiliation><nlm:aff id="Aff86">Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 USA</nlm:aff></affiliation></author><author><name sortKey="Van Rensburg, Elizabeth J" sort="Van Rensburg, Elizabeth J" uniqKey="Van Rensburg E" first="Elizabeth J." last="Van Rensburg">Elizabeth J. Van Rensburg</name><affiliation><nlm:aff id="Aff87">Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007 South Africa</nlm:aff></affiliation></author><author><name sortKey="Villano, Danylo" sort="Villano, Danylo" uniqKey="Villano D" first="Danylo" last="Villano">Danylo Villano</name><affiliation><nlm:aff id="Aff88">Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY USA</nlm:aff></affiliation></author><author><name sortKey="Wang Gohrke, Shan" sort="Wang Gohrke, Shan" uniqKey="Wang Gohrke S" first="Shan" last="Wang-Gohrke">Shan Wang-Gohrke</name><affiliation><nlm:aff id="Aff89">Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany</nlm:aff></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation><nlm:aff id="Aff38">Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Weitzel, Jeffrey N" sort="Weitzel, Jeffrey N" uniqKey="Weitzel J" first="Jeffrey N." last="Weitzel">Jeffrey N. 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Zorn</name><affiliation><nlm:aff id="Aff93">4301 West Markham Street, Slot 793, Little Rock, AR 72205 USA</nlm:aff></affiliation></author><author><name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name><affiliation><nlm:aff id="Aff6">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas" sort="Easton, Douglas" uniqKey="Easton D" first="Douglas" last="Easton">Douglas Easton</name><affiliation><nlm:aff id="Aff6">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation><nlm:aff id="Aff5">Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Antoniou, Antonis C" sort="Antoniou, Antonis C" uniqKey="Antoniou A" first="Antonis C." last="Antoniou">Antonis C. 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Ramus</name><affiliation><nlm:aff id="Aff4">Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff94">Present Address: School of Women’s and Children’s Health, University of New South Wales and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010 Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27836010</idno><idno type="pmc">5106833</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106833</idno><idno type="RBID">PMC:5106833</idno><idno type="doi">10.1186/s13058-016-0768-3</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000B44</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B44</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Inheritance of deleterious mutations at both <italic>BRCA1</italic> and <italic>BRCA2</italic> in an international sample of 32,295 women</title><author><name sortKey="Rebbeck, Timothy R" sort="Rebbeck, Timothy R" uniqKey="Rebbeck T" first="Timothy R." last="Rebbeck">Timothy R. Rebbeck</name><affiliation><nlm:aff id="Aff1">Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</nlm:aff></affiliation></author><author><name sortKey="Friebel, Tara M" sort="Friebel, Tara M" uniqKey="Friebel T" first="Tara M." last="Friebel">Tara M. Friebel</name><affiliation><nlm:aff id="Aff1">Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</nlm:aff></affiliation></author><author><name sortKey="Mitra, Nandita" sort="Mitra, Nandita" uniqKey="Mitra N" first="Nandita" last="Mitra">Nandita Mitra</name><affiliation><nlm:aff id="Aff2">Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</nlm:aff></affiliation></author><author><name sortKey="Wan, Fei" sort="Wan, Fei" uniqKey="Wan F" first="Fei" last="Wan">Fei Wan</name><affiliation><nlm:aff id="Aff3">Biostatistics Unit, Group Health Research Institute, Seattle, WA USA</nlm:aff></affiliation></author><author><name sortKey="Chen, Stephanie" sort="Chen, Stephanie" uniqKey="Chen S" first="Stephanie" last="Chen">Stephanie Chen</name><affiliation><nlm:aff id="Aff4">Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA</nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="Aff7">Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8">Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario Canada</nlm:aff></affiliation></author><author><name sortKey="Apostolou, Paraskevi" sort="Apostolou, Paraskevi" uniqKey="Apostolou P" first="Paraskevi" last="Apostolou">Paraskevi Apostolou</name><affiliation><nlm:aff id="Aff9">Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research “Demokritos”, Patriarchou Gregoriou & Neapoleos str. Aghia Paraskevi Attikis, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Arnold, Norbert" sort="Arnold, Norbert" uniqKey="Arnold N" first="Norbert" last="Arnold">Norbert Arnold</name><affiliation><nlm:aff id="Aff10">Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Arun, Banu K" sort="Arun, Banu K" uniqKey="Arun B" first="Banu K." last="Arun">Banu K. Arun</name><affiliation><nlm:aff id="Aff11">Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX USA</nlm:aff></affiliation></author><author><name sortKey="Barrowdale, Daniel" sort="Barrowdale, Daniel" uniqKey="Barrowdale D" first="Daniel" last="Barrowdale">Daniel Barrowdale</name><affiliation><nlm:aff id="Aff5">Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benitez">Javier Benitez</name><affiliation><nlm:aff id="Aff12">Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="Aff13">Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14">Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Berger, Raanan" sort="Berger, Raanan" uniqKey="Berger R" first="Raanan" last="Berger">Raanan Berger</name><affiliation><nlm:aff id="Aff15">The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation></author><author><name sortKey="Berthet, Pascaline" sort="Berthet, Pascaline" uniqKey="Berthet P" first="Pascaline" last="Berthet">Pascaline Berthet</name><affiliation><nlm:aff id="Aff16">Centre François Baclesse, 3 avenue Général Harris, Caen, France</nlm:aff></affiliation></author><author><name sortKey="Borg, Ake" sort="Borg, Ake" uniqKey="Borg A" first="Ake" last="Borg">Ake Borg</name><affiliation><nlm:aff id="Aff17">Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Buys, Saundra S" sort="Buys, Saundra S" uniqKey="Buys S" first="Saundra S." last="Buys">Saundra S. Buys</name><affiliation><nlm:aff id="Aff18">Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112 USA</nlm:aff></affiliation></author><author><name sortKey="Caldes, Trinidad" sort="Caldes, Trinidad" uniqKey="Caldes T" first="Trinidad" last="Caldes">Trinidad Caldes</name><affiliation><nlm:aff id="Aff19">Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Carter, Jonathan" sort="Carter, Jonathan" uniqKey="Carter J" first="Jonathan" last="Carter">Jonathan Carter</name><affiliation><nlm:aff id="Aff20">Gynaecological Oncology, The University of Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Chiquette, Jocelyne" sort="Chiquette, Jocelyne" uniqKey="Chiquette J" first="Jocelyne" last="Chiquette">Jocelyne Chiquette</name><affiliation><nlm:aff id="Aff21">Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050 chemin Sainte-Foy, Québec Canada</nlm:aff></affiliation></author><author><name sortKey="Claes, Kathleen B M" sort="Claes, Kathleen B M" uniqKey="Claes K" first="Kathleen B. M." last="Claes">Kathleen B. M. Claes</name><affiliation><nlm:aff id="Aff22">Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000 Gent, Belgium</nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="Aff23">Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota USA</nlm:aff></affiliation></author><author><name sortKey="Cybulski, Cezary" sort="Cybulski, Cezary" uniqKey="Cybulski C" first="Cezary" last="Cybulski">Cezary Cybulski</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Daly, Mary B" sort="Daly, Mary B" uniqKey="Daly M" first="Mary B." last="Daly">Mary B. Daly</name><affiliation><nlm:aff id="Aff25">Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 USA</nlm:aff></affiliation></author><author><name sortKey="De La Hoya, Miguel" sort="De La Hoya, Miguel" uniqKey="De La Hoya M" first="Miguel" last="De La Hoya">Miguel De La Hoya</name><affiliation><nlm:aff id="Aff19">Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Diez, Orland" sort="Diez, Orland" uniqKey="Diez O" first="Orland" last="Diez">Orland Diez</name><affiliation><nlm:aff id="Aff26">Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Domchek, Susan M" sort="Domchek, Susan M" uniqKey="Domchek S" first="Susan M." last="Domchek">Susan M. Domchek</name><affiliation><nlm:aff id="Aff27">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</nlm:aff></affiliation></author><author><name sortKey="Nathanson, Katherine L" sort="Nathanson, Katherine L" uniqKey="Nathanson K" first="Katherine L." last="Nathanson">Katherine L. Nathanson</name><affiliation><nlm:aff id="Aff27">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</nlm:aff></affiliation></author><author><name sortKey="Durda, Katarzyna" sort="Durda, Katarzyna" uniqKey="Durda K" first="Katarzyna" last="Durda">Katarzyna Durda</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Ellis, Steve" sort="Ellis, Steve" uniqKey="Ellis S" first="Steve" last="Ellis">Steve Ellis</name><affiliation><nlm:aff id="Aff28">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Evans, D Gareth" sort="Evans, D Gareth" uniqKey="Evans D" first="D. Gareth" last="Evans">D. Gareth Evans</name><affiliation><nlm:aff id="Aff29">Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Foretova, Lenka" sort="Foretova, Lenka" uniqKey="Foretova L" first="Lenka" last="Foretova">Lenka Foretova</name><affiliation><nlm:aff id="Aff30">Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653 Czech Republic</nlm:aff></affiliation></author><author><name sortKey="Friedman, Eitan" sort="Friedman, Eitan" uniqKey="Friedman E" first="Eitan" last="Friedman">Eitan Friedman</name><affiliation><nlm:aff id="Aff31">The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff32">Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel</nlm:aff></affiliation></author><author><name sortKey="Frost, Debra" sort="Frost, Debra" uniqKey="Frost D" first="Debra" last="Frost">Debra Frost</name><affiliation><nlm:aff id="Aff28">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Ganz, Patricia A" sort="Ganz, Patricia A" uniqKey="Ganz P" first="Patricia A." last="Ganz">Patricia A. Ganz</name><affiliation><nlm:aff id="Aff33">UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA 90095-6900 USA</nlm:aff></affiliation></author><author><name sortKey="Garber, Judy" sort="Garber, Judy" uniqKey="Garber J" first="Judy" last="Garber">Judy Garber</name><affiliation><nlm:aff id="Aff1">Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</nlm:aff></affiliation></author><author><name sortKey="Glendon, Gord" sort="Glendon, Gord" uniqKey="Glendon G" first="Gord" last="Glendon">Gord Glendon</name><affiliation><nlm:aff id="Aff34">Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada</nlm:aff></affiliation></author><author><name sortKey="Godwin, Andrew K" sort="Godwin, Andrew K" uniqKey="Godwin A" first="Andrew K." last="Godwin">Andrew K. Godwin</name><affiliation><nlm:aff id="Aff35">Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS 3040 Kansas, USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff36">University of Kansas Medical Center, Kansas City, Kansas USA</nlm:aff></affiliation></author><author><name sortKey="Greene, Mark H" sort="Greene, Mark H" uniqKey="Greene M" first="Mark H." last="Greene">Mark H. Greene</name><affiliation><nlm:aff id="Aff37">Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD USA</nlm:aff></affiliation></author><author><name sortKey="Gronwald, Jacek" sort="Gronwald, Jacek" uniqKey="Gronwald J" first="Jacek" last="Gronwald">Jacek Gronwald</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Hahnen, Eric" sort="Hahnen, Eric" uniqKey="Hahnen E" first="Eric" last="Hahnen">Eric Hahnen</name><affiliation><nlm:aff id="Aff38">Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Hallberg, Emily" sort="Hallberg, Emily" uniqKey="Hallberg E" first="Emily" last="Hallberg">Emily Hallberg</name><affiliation><nlm:aff id="Aff39">Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ USA</nlm:aff></affiliation></author><author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name><affiliation><nlm:aff id="Aff40">Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Hansen, Thomas V O" sort="Hansen, Thomas V O" uniqKey="Hansen T" first="Thomas V. O." last="Hansen">Thomas V. O. Hansen</name><affiliation><nlm:aff id="Aff41">Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Imyanitov, Evgeny N" sort="Imyanitov, Evgeny N" uniqKey="Imyanitov E" first="Evgeny N." last="Imyanitov">Evgeny N. Imyanitov</name><affiliation><nlm:aff id="Aff43">N.N. Petrov Institute of Oncology, St.-Petersburg, 197758 Russia</nlm:aff></affiliation></author><author><name sortKey="Isaacs, Claudine" sort="Isaacs, Claudine" uniqKey="Isaacs C" first="Claudine" last="Isaacs">Claudine Isaacs</name><affiliation><nlm:aff id="Aff44">Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC USA</nlm:aff></affiliation></author><author><name sortKey="Jakubowska, Anna" sort="Jakubowska, Anna" uniqKey="Jakubowska A" first="Anna" last="Jakubowska">Anna Jakubowska</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Janavicius, Ramunas" sort="Janavicius, Ramunas" uniqKey="Janavicius R" first="Ramunas" last="Janavicius">Ramunas Janavicius</name><affiliation><nlm:aff id="Aff45">Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Santariskiu st, Vilnius, Lithuania</nlm:aff></affiliation><affiliation><nlm:aff id="Aff46">State Research Institute Centre for Innovative medicine, Zygymantu st. 9, Vilnius, Lithuania</nlm:aff></affiliation></author><author><name sortKey="Jaworska Bieniek, Katarzyna" sort="Jaworska Bieniek, Katarzyna" uniqKey="Jaworska Bieniek K" first="Katarzyna" last="Jaworska-Bieniek">Katarzyna Jaworska-Bieniek</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="Aff47">Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538 USA</nlm:aff></affiliation></author><author><name sortKey="Karlan, Beth Y" sort="Karlan, Beth Y" uniqKey="Karlan B" first="Beth Y." last="Karlan">Beth Y. Karlan</name><affiliation><nlm:aff id="Aff48">Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA USA</nlm:aff></affiliation></author><author><name sortKey="Kaufman, Bella" sort="Kaufman, Bella" uniqKey="Kaufman B" first="Bella" last="Kaufman">Bella Kaufman</name><affiliation><nlm:aff id="Aff15">The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation></author><author><name sortKey="Investigators, Kconfab" sort="Investigators, Kconfab" uniqKey="Investigators K" first="Kconfab" last="Investigators">Kconfab Investigators</name><affiliation><nlm:aff id="Aff49">Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Kwong, Ava" sort="Kwong, Ava" uniqKey="Kwong A" first="Ava" last="Kwong">Ava Kwong</name><affiliation><nlm:aff id="Aff50">The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong</nlm:aff></affiliation><affiliation><nlm:aff id="Aff51">Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong</nlm:aff></affiliation></author><author><name sortKey="Laitman, Yael" sort="Laitman, Yael" uniqKey="Laitman Y" first="Yael" last="Laitman">Yael Laitman</name><affiliation><nlm:aff id="Aff31">The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff32">Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel</nlm:aff></affiliation></author><author><name sortKey="Lasset, Christine" sort="Lasset, Christine" uniqKey="Lasset C" first="Christine" last="Lasset">Christine Lasset</name><affiliation><nlm:aff id="Aff52">Unité de Prévention et d’Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Lazaro, Conxi" sort="Lazaro, Conxi" uniqKey="Lazaro C" first="Conxi" last="Lazaro">Conxi Lazaro</name><affiliation><nlm:aff id="Aff53">Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute) Catalan Institute of Oncology, Gran Via de l’Hospitalet, 199-203, 08908, L’Hospitalet Barcelona, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Lester, Jenny" sort="Lester, Jenny" uniqKey="Lester J" first="Jenny" last="Lester">Jenny Lester</name><affiliation><nlm:aff id="Aff48">Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA USA</nlm:aff></affiliation></author><author><name sortKey="Loman, Niklas" sort="Loman, Niklas" uniqKey="Loman N" first="Niklas" last="Loman">Niklas Loman</name><affiliation><nlm:aff id="Aff54">Department of Oncology, Lund University Hospital, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lubinski, Jan" sort="Lubinski, Jan" uniqKey="Lubinski J" first="Jan" last="Lubinski">Jan Lubinski</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Manoukian, Siranoush" sort="Manoukian, Siranoush" uniqKey="Manoukian S" first="Siranoush" last="Manoukian">Siranoush Manoukian</name><affiliation><nlm:aff id="Aff55">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Mitchell, Gillian" sort="Mitchell, Gillian" uniqKey="Mitchell G" first="Gillian" last="Mitchell">Gillian Mitchell</name><affiliation><nlm:aff id="Aff56">Familial Cancer Centre, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006 Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff57">Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052 Australia</nlm:aff></affiliation></author><author><name sortKey="Montagna, Marco" sort="Montagna, Marco" uniqKey="Montagna M" first="Marco" last="Montagna">Marco Montagna</name><affiliation><nlm:aff id="Aff58">Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOC - IRCCS, Via Gattamelata 64, Padua, Italy</nlm:aff></affiliation></author><author><name sortKey="Neuhausen, Susan L" sort="Neuhausen, Susan L" uniqKey="Neuhausen S" first="Susan L." last="Neuhausen">Susan L. Neuhausen</name><affiliation><nlm:aff id="Aff59">Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA USA</nlm:aff></affiliation></author><author><name sortKey="Nevanlinna, Heli" sort="Nevanlinna, Heli" uniqKey="Nevanlinna H" first="Heli" last="Nevanlinna">Heli Nevanlinna</name><affiliation><nlm:aff id="Aff60">Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700, (Haartmaninkatu 8), 00029 HUS Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Niederacher, Dieter" sort="Niederacher, Dieter" uniqKey="Niederacher D" first="Dieter" last="Niederacher">Dieter Niederacher</name><affiliation><nlm:aff id="Aff61">Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany</nlm:aff></affiliation></author><author><name sortKey="Nussbaum, Robert L" sort="Nussbaum, Robert L" uniqKey="Nussbaum R" first="Robert L." last="Nussbaum">Robert L. Nussbaum</name><affiliation><nlm:aff id="Aff62">513 Parnassus Ave., HSE 901E, San Francisco, CA 94143-0794 USA</nlm:aff></affiliation></author><author><name sortKey="Offit, Kenneth" sort="Offit, Kenneth" uniqKey="Offit K" first="Kenneth" last="Offit">Kenneth Offit</name><affiliation><nlm:aff id="Aff63">Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10044 USA</nlm:aff></affiliation></author><author><name sortKey="Olah, Edith" sort="Olah, Edith" uniqKey="Olah E" first="Edith" last="Olah">Edith Olah</name><affiliation><nlm:aff id="Aff64">Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary</nlm:aff></affiliation></author><author><name sortKey="Olopade, Olufunmilayo I" sort="Olopade, Olufunmilayo I" uniqKey="Olopade O" first="Olufunmilayo I." last="Olopade">Olufunmilayo I. Olopade</name><affiliation><nlm:aff id="Aff65">5841 South Maryland Avenue, MC 2115 Chicago, IL USA</nlm:aff></affiliation></author><author><name sortKey="Park, Sue Kyung" sort="Park, Sue Kyung" uniqKey="Park S" first="Sue Kyung" last="Park">Sue Kyung Park</name><affiliation><nlm:aff id="Aff66">Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 Korea</nlm:aff></affiliation></author><author><name sortKey="Piedmonte, Marion" sort="Piedmonte, Marion" uniqKey="Piedmonte M" first="Marion" last="Piedmonte">Marion Piedmonte</name><affiliation><nlm:aff id="Aff67">NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY 14263 USA</nlm:aff></affiliation></author><author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name><affiliation><nlm:aff id="Aff68">Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133 Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Rappaport Fuerhauser, Christine" sort="Rappaport Fuerhauser, Christine" uniqKey="Rappaport Fuerhauser C" first="Christine" last="Rappaport-Fuerhauser">Christine Rappaport-Fuerhauser</name><affiliation><nlm:aff id="Aff69">Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Rookus, Matti A" sort="Rookus, Matti A" uniqKey="Rookus M" first="Matti A." last="Rookus">Matti A. Rookus</name><affiliation><nlm:aff id="Aff70">Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000 BE Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Seynaeve, Caroline" sort="Seynaeve, Caroline" uniqKey="Seynaeve C" first="Caroline" last="Seynaeve">Caroline Seynaeve</name><affiliation><nlm:aff id="Aff71">Department of Medical Oncology, Family Cancer Clinic Erasmus University Medical Center Cancer institute, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name><affiliation><nlm:aff id="Aff72">Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec Canada</nlm:aff></affiliation></author><author><name sortKey="Singer, Christian F" sort="Singer, Christian F" uniqKey="Singer C" first="Christian F." last="Singer">Christian F. Singer</name><affiliation><nlm:aff id="Aff73">Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Soucy, Penny" sort="Soucy, Penny" uniqKey="Soucy P" first="Penny" last="Soucy">Penny Soucy</name><affiliation><nlm:aff id="Aff72">Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec Canada</nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa" sort="Southey, Melissa" uniqKey="Southey M" first="Melissa" last="Southey">Melissa Southey</name><affiliation><nlm:aff id="Aff74">Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria Australia</nlm:aff></affiliation></author><author><name sortKey="Stoppa Lyonnet, Dominique" sort="Stoppa Lyonnet, Dominique" uniqKey="Stoppa Lyonnet D" first="Dominique" last="Stoppa-Lyonnet">Dominique Stoppa-Lyonnet</name><affiliation><nlm:aff id="Aff75">Service de Génétique Oncologique, Institut Curie, 26, rue d’Ulm, Paris, Cedex 05, France</nlm:aff></affiliation></author><author><name sortKey="Sukiennicki, Grzegorz" sort="Sukiennicki, Grzegorz" uniqKey="Sukiennicki G" first="Grzegorz" last="Sukiennicki">Grzegorz Sukiennicki</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Szabo, Csilla I" sort="Szabo, Csilla I" uniqKey="Szabo C" first="Csilla I." last="Szabo">Csilla I. Szabo</name><affiliation><nlm:aff id="Aff76">National Human Genome Research Institute, National Institutes of Health Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD 20892-8004 USA</nlm:aff></affiliation></author><author><name sortKey="Tancredi, Mariella" sort="Tancredi, Mariella" uniqKey="Tancredi M" first="Mariella" last="Tancredi">Mariella Tancredi</name><affiliation><nlm:aff id="Aff77">Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Teixeira, Manuel R" sort="Teixeira, Manuel R" uniqKey="Teixeira M" first="Manuel R." last="Teixeira">Manuel R. Teixeira</name><affiliation><nlm:aff id="Aff78">Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal</nlm:aff></affiliation></author><author><name sortKey="Teo, Soo Hwang" sort="Teo, Soo Hwang" uniqKey="Teo S" first="Soo-Hwang" last="Teo">Soo-Hwang Teo</name><affiliation><nlm:aff id="Aff79">Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Malaysia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff80">University Malaya Cancer Research Institute, University Malaya, 50603 Kuala Lumpur, Malaysia</nlm:aff></affiliation></author><author><name sortKey="Terry, Mary Beth" sort="Terry, Mary Beth" uniqKey="Terry M" first="Mary Beth" last="Terry">Mary Beth Terry</name><affiliation><nlm:aff id="Aff81">Department of Epidemiology, Columbia University, New York, NY USA</nlm:aff></affiliation></author><author><name sortKey="Thomassen, Mads" sort="Thomassen, Mads" uniqKey="Thomassen M" first="Mads" last="Thomassen">Mads Thomassen</name><affiliation><nlm:aff id="Aff82">Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark</nlm:aff></affiliation></author><author><name sortKey="Tihomirova, Laima" sort="Tihomirova, Laima" uniqKey="Tihomirova L" first="Laima" last="Tihomirova">Laima Tihomirova</name><affiliation><nlm:aff id="Aff83">Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia</nlm:aff></affiliation></author><author><name sortKey="Tischkowitz, Marc" sort="Tischkowitz, Marc" uniqKey="Tischkowitz M" first="Marc" last="Tischkowitz">Marc Tischkowitz</name><affiliation><nlm:aff id="Aff84">Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec Canada</nlm:aff></affiliation></author><author><name sortKey="Toland, Amanda Ewart" sort="Toland, Amanda Ewart" uniqKey="Toland A" first="Amanda Ewart" last="Toland">Amanda Ewart Toland</name><affiliation><nlm:aff id="Aff85">Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH USA</nlm:aff></affiliation></author><author><name sortKey="Toloczko Grabarek, Aleksandra" sort="Toloczko Grabarek, Aleksandra" uniqKey="Toloczko Grabarek A" first="Aleksandra" last="Toloczko-Grabarek">Aleksandra Toloczko-Grabarek</name><affiliation><nlm:aff id="Aff24">Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Tung, Nadine" sort="Tung, Nadine" uniqKey="Tung N" first="Nadine" last="Tung">Nadine Tung</name><affiliation><nlm:aff id="Aff86">Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 USA</nlm:aff></affiliation></author><author><name sortKey="Van Rensburg, Elizabeth J" sort="Van Rensburg, Elizabeth J" uniqKey="Van Rensburg E" first="Elizabeth J." last="Van Rensburg">Elizabeth J. Van Rensburg</name><affiliation><nlm:aff id="Aff87">Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007 South Africa</nlm:aff></affiliation></author><author><name sortKey="Villano, Danylo" sort="Villano, Danylo" uniqKey="Villano D" first="Danylo" last="Villano">Danylo Villano</name><affiliation><nlm:aff id="Aff88">Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY USA</nlm:aff></affiliation></author><author><name sortKey="Wang Gohrke, Shan" sort="Wang Gohrke, Shan" uniqKey="Wang Gohrke S" first="Shan" last="Wang-Gohrke">Shan Wang-Gohrke</name><affiliation><nlm:aff id="Aff89">Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany</nlm:aff></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation><nlm:aff id="Aff38">Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany</nlm:aff></affiliation></author><author><name sortKey="Weitzel, Jeffrey N" sort="Weitzel, Jeffrey N" uniqKey="Weitzel J" first="Jeffrey N." last="Weitzel">Jeffrey N. Weitzel</name><affiliation><nlm:aff id="Aff90">Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California 91010 USA</nlm:aff></affiliation></author><author><name sortKey="Zidan, Jamal" sort="Zidan, Jamal" uniqKey="Zidan J" first="Jamal" last="Zidan">Jamal Zidan</name><affiliation><nlm:aff id="Aff91">Institute of Oncology, Rivka Ziv Medical Center, 13000 Zefat, Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff92">The Faculty of Medicine, Bar-Ilan University, Zefat, Israel</nlm:aff></affiliation></author><author><name sortKey="Zorn, Kristin K" sort="Zorn, Kristin K" uniqKey="Zorn K" first="Kristin K." last="Zorn">Kristin K. Zorn</name><affiliation><nlm:aff id="Aff93">4301 West Markham Street, Slot 793, Little Rock, AR 72205 USA</nlm:aff></affiliation></author><author><name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name><affiliation><nlm:aff id="Aff6">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas" sort="Easton, Douglas" uniqKey="Easton D" first="Douglas" last="Easton">Douglas Easton</name><affiliation><nlm:aff id="Aff6">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation><nlm:aff id="Aff5">Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Antoniou, Antonis C" sort="Antoniou, Antonis C" uniqKey="Antoniou A" first="Antonis C." last="Antoniou">Antonis C. Antoniou</name><affiliation><nlm:aff id="Aff6">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Ramus, Susan J" sort="Ramus, Susan J" uniqKey="Ramus S" first="Susan J." last="Ramus">Susan J. Ramus</name><affiliation><nlm:aff id="Aff4">Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff94">Present Address: School of Women’s and Children’s Health, University of New South Wales and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010 Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Breast Cancer Research : BCR</title><idno type="ISSN">1465-5411</idno><idno type="eISSN">1465-542X</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Most <italic>BRCA1</italic> or <italic>BRCA2</italic> mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both <italic>BRCA1</italic> and <italic>BRCA2</italic> are rare, and the consequences of transheterozygosity are poorly understood.</p></sec><sec><title>Methods</title><p>From 32,295 female <italic>BRCA1/2</italic> mutation carriers, we identified 93 TH (0.3 %). “Cases” were defined as TH, and “controls” were single mutations at <italic>BRCA1</italic> (SH1) or <italic>BRCA2</italic> (SH2). Matched SH1 “controls” carried a BRCA1 mutation found in the TH “case”. Matched SH2 “controls” carried a BRCA2 mutation found in the TH “case”. After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.</p></sec><sec><title>Results</title><p>The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; <italic>p</italic> = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (<italic>p</italic> = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (<italic>p</italic> = 0.231), but was on average 4.5 years younger in TH than in SH2 (<italic>p</italic> < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (<italic>p</italic> = 0.010) or progesterone receptor (PR) positive (<italic>p</italic> = 0.013) than in SH1, but less likely to be ER positive (<italic>p</italic> < 0.001) or PR positive (<italic>p</italic> = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for <italic>BRCA1</italic> or <italic>BRCA2</italic> in either BC or OC.</p></sec><sec><title>Conclusions</title><p>Our observations suggest that clinical TH phenotypes resemble SH1. 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rid="Aff57">57</xref></contrib><contrib contrib-type="author"><name><surname>Montagna</surname><given-names>Marco</given-names></name><address><email>marco.montagna@ioveneto.it</email></address><xref ref-type="aff" rid="Aff58">58</xref></contrib><contrib contrib-type="author"><name><surname>Neuhausen</surname><given-names>Susan L.</given-names></name><address><email>sneuhausen@coh.org</email></address><xref ref-type="aff" rid="Aff59">59</xref></contrib><contrib contrib-type="author"><name><surname>Nevanlinna</surname><given-names>Heli</given-names></name><address><email>heli.nevanlinna@hus.fi</email></address><xref ref-type="aff" rid="Aff60">60</xref></contrib><contrib contrib-type="author"><name><surname>Niederacher</surname><given-names>Dieter</given-names></name><address><email>niederac@med.uni-duesseldorf.de</email></address><xref ref-type="aff" rid="Aff61">61</xref></contrib><contrib contrib-type="author"><name><surname>Nussbaum</surname><given-names>Robert L.</given-names></name><address><email>nussbaumr@humgen.ucsf.edu</email></address><xref ref-type="aff" rid="Aff62">62</xref></contrib><contrib contrib-type="author"><name><surname>Offit</surname><given-names>Kenneth</given-names></name><address><email>offitk@mskcc.org</email></address><xref ref-type="aff" rid="Aff63">63</xref></contrib><contrib contrib-type="author"><name><surname>Olah</surname><given-names>Edith</given-names></name><address><email>e.olah@oncol.hu</email></address><xref ref-type="aff" rid="Aff64">64</xref></contrib><contrib contrib-type="author"><name><surname>Olopade</surname><given-names>Olufunmilayo I.</given-names></name><address><email>folopade@medicine.bsd.uchicago.edu</email></address><xref ref-type="aff" rid="Aff65">65</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Sue Kyung</given-names></name><address><email>suepark@snu.ac.kr</email></address><xref ref-type="aff" rid="Aff66">66</xref></contrib><contrib contrib-type="author"><name><surname>Piedmonte</surname><given-names>Marion</given-names></name><xref ref-type="aff" rid="Aff67">67</xref></contrib><contrib contrib-type="author"><name><surname>Radice</surname><given-names>Paolo</given-names></name><address><email>paolo.radice@istitutotumori.mi.it</email></address><xref ref-type="aff" rid="Aff68">68</xref></contrib><contrib contrib-type="author"><name><surname>Rappaport-Fuerhauser</surname><given-names>Christine</given-names></name><address><email>christine.rappaport@akhwien.at</email></address><xref ref-type="aff" rid="Aff69">69</xref></contrib><contrib contrib-type="author"><name><surname>Rookus</surname><given-names>Matti A.</given-names></name><xref ref-type="aff" rid="Aff70">70</xref></contrib><contrib contrib-type="author"><name><surname>Seynaeve</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="Aff71">71</xref></contrib><contrib contrib-type="author"><name><surname>Simard</surname><given-names>Jacques</given-names></name><address><email>Jacques.Simard@crchul.ulaval.ca</email></address><xref ref-type="aff" rid="Aff72">72</xref></contrib><contrib contrib-type="author"><name><surname>Singer</surname><given-names>Christian F.</given-names></name><xref ref-type="aff" rid="Aff73">73</xref></contrib><contrib contrib-type="author"><name><surname>Soucy</surname><given-names>Penny</given-names></name><address><email>Penny.Soucy@crchul.ulaval.ca</email></address><xref ref-type="aff" rid="Aff72">72</xref></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>Melissa</given-names></name><address><email>msouthey@unimelb.edu.au</email></address><xref ref-type="aff" rid="Aff74">74</xref></contrib><contrib contrib-type="author"><name><surname>Stoppa-Lyonnet</surname><given-names>Dominique</given-names></name><address><email>dominique.stoppa-lyonnet@curie.fr</email></address><xref ref-type="aff" rid="Aff75">75</xref></contrib><contrib contrib-type="author"><name><surname>Sukiennicki</surname><given-names>Grzegorz</given-names></name><address><email>starosta84@wp.pl</email></address><xref ref-type="aff" rid="Aff24">24</xref></contrib><contrib contrib-type="author"><name><surname>Szabo</surname><given-names>Csilla I.</given-names></name><address><email>szaboc@mail.nih.gov</email></address><xref ref-type="aff" rid="Aff76">76</xref></contrib><contrib contrib-type="author"><name><surname>Tancredi</surname><given-names>Mariella</given-names></name><xref ref-type="aff" rid="Aff77">77</xref></contrib><contrib contrib-type="author"><name><surname>Teixeira</surname><given-names>Manuel R.</given-names></name><address><email>manuel.teixeira@ipoporto.min-saude.pt</email></address><xref ref-type="aff" rid="Aff78">78</xref></contrib><contrib contrib-type="author"><name><surname>Teo</surname><given-names>Soo-Hwang</given-names></name><address><email>soohwang.teo@carif.com.my</email></address><xref ref-type="aff" rid="Aff79">79</xref><xref ref-type="aff" rid="Aff80">80</xref></contrib><contrib contrib-type="author"><name><surname>Terry</surname><given-names>Mary Beth</given-names></name><address><email>mt146@cumc.columbia.edu</email></address><xref ref-type="aff" rid="Aff81">81</xref></contrib><contrib contrib-type="author"><name><surname>Thomassen</surname><given-names>Mads</given-names></name><address><email>mads.thomassen@rsyd.dk</email></address><xref ref-type="aff" rid="Aff82">82</xref></contrib><contrib contrib-type="author"><name><surname>Tihomirova</surname><given-names>Laima</given-names></name><xref ref-type="aff" rid="Aff83">83</xref></contrib><contrib contrib-type="author"><name><surname>Tischkowitz</surname><given-names>Marc</given-names></name><address><email>mdt33@medschl.cam.ac.uk</email></address><xref ref-type="aff" rid="Aff84">84</xref></contrib><contrib contrib-type="author"><name><surname>Toland</surname><given-names>Amanda Ewart</given-names></name><address><email>amanda.toland@osumc.edu</email></address><xref ref-type="aff" rid="Aff85">85</xref></contrib><contrib contrib-type="author"><name><surname>Toloczko-Grabarek</surname><given-names>Aleksandra</given-names></name><xref ref-type="aff" rid="Aff24">24</xref></contrib><contrib contrib-type="author"><name><surname>Tung</surname><given-names>Nadine</given-names></name><address><email>ntung@bidmc.harvard.edu</email></address><xref ref-type="aff" rid="Aff86">86</xref></contrib><contrib contrib-type="author"><name><surname>van Rensburg</surname><given-names>Elizabeth J.</given-names></name><address><email>Lizette.vanrensburg@up.ac.za</email></address><xref ref-type="aff" rid="Aff87">87</xref></contrib><contrib contrib-type="author"><name><surname>Villano</surname><given-names>Danylo</given-names></name><xref ref-type="aff" rid="Aff88">88</xref></contrib><contrib contrib-type="author"><name><surname>Wang-Gohrke</surname><given-names>Shan</given-names></name><address><email>shan.wang-gohrke@uniklinik-ulm.de</email></address><xref ref-type="aff" rid="Aff89">89</xref></contrib><contrib contrib-type="author"><name><surname>Wappenschmidt</surname><given-names>Barbara</given-names></name><address><email>Barbara.Wappenschmidt@uk-koeln.de</email></address><xref ref-type="aff" rid="Aff38">38</xref></contrib><contrib contrib-type="author"><name><surname>Weitzel</surname><given-names>Jeffrey N.</given-names></name><address><email>jweitzel@coh.org</email></address><xref ref-type="aff" rid="Aff90">90</xref></contrib><contrib contrib-type="author"><name><surname>Zidan</surname><given-names>Jamal</given-names></name><xref ref-type="aff" rid="Aff91">91</xref><xref ref-type="aff" rid="Aff92">92</xref></contrib><contrib contrib-type="author"><name><surname>Zorn</surname><given-names>Kristin K.</given-names></name><xref ref-type="aff" rid="Aff93">93</xref></contrib><contrib contrib-type="author"><name><surname>McGuffog</surname><given-names>Lesley</given-names></name><address><email>lesley@srl.cam.ac.uk</email></address><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Douglas</given-names></name><address><email>douglas@srl.cam.ac.uk</email></address><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Chenevix-Trench</surname><given-names>Georgia</given-names></name><address><email>Georgia.Trench@qimrberghofer.edu.au</email></address><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Antoniou</surname><given-names>Antonis C.</given-names></name><address><email>antonis@srl.cam.ac.uk</email></address><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Ramus</surname><given-names>Susan J.</given-names></name><address><email>s.ramus@unsw.edu.au</email></address><xref ref-type="aff" rid="Aff4">4</xref><xref ref-type="aff" rid="Aff94">94</xref></contrib><aff id="Aff1"><label>1</label>Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA USA</aff><aff id="Aff2"><label>2</label>Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</aff><aff id="Aff3"><label>3</label>Biostatistics Unit, Group Health Research Institute, Seattle, WA USA</aff><aff id="Aff4"><label>4</label>Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA</aff><aff id="Aff5"><label>5</label>Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia</aff><aff id="Aff6"><label>6</label>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK</aff><aff id="Aff7"><label>7</label>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada</aff><aff id="Aff8"><label>8</label>Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario Canada</aff><aff id="Aff9"><label>9</label>Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research “Demokritos”, Patriarchou Gregoriou & Neapoleos str. Aghia Paraskevi Attikis, Athens, Greece</aff><aff id="Aff10"><label>10</label>Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University, Kiel, Germany</aff><aff id="Aff11"><label>11</label>Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX USA</aff><aff id="Aff12"><label>12</label>Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain</aff><aff id="Aff13"><label>13</label>Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain</aff><aff id="Aff14"><label>14</label>Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain</aff><aff id="Aff15"><label>15</label>The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</aff><aff id="Aff16"><label>16</label>Centre François Baclesse, 3 avenue Général Harris, Caen, France</aff><aff id="Aff17"><label>17</label>Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden</aff><aff id="Aff18"><label>18</label>Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112 USA</aff><aff id="Aff19"><label>19</label>Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain</aff><aff id="Aff20"><label>20</label>Gynaecological Oncology, The University of Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia</aff><aff id="Aff21"><label>21</label>Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050 chemin Sainte-Foy, Québec Canada</aff><aff id="Aff22"><label>22</label>Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000 Gent, Belgium</aff><aff id="Aff23"><label>23</label>Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota USA</aff><aff id="Aff24"><label>24</label>Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland</aff><aff id="Aff25"><label>25</label>Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 USA</aff><aff id="Aff26"><label>26</label>Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, Barcelona, Spain</aff><aff id="Aff27"><label>27</label>Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA</aff><aff id="Aff28"><label>28</label>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK</aff><aff id="Aff29"><label>29</label>Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</aff><aff id="Aff30"><label>30</label>Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653 Czech Republic</aff><aff id="Aff31"><label>31</label>The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621 Israel</aff><aff id="Aff32"><label>32</label>Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel</aff><aff id="Aff33"><label>33</label>UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA 90095-6900 USA</aff><aff id="Aff34"><label>34</label>Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada</aff><aff id="Aff35"><label>35</label>Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS 3040 Kansas, USA</aff><aff id="Aff36"><label>36</label>University of Kansas Medical Center, Kansas City, Kansas USA</aff><aff id="Aff37"><label>37</label>Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD USA</aff><aff id="Aff38"><label>38</label>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany</aff><aff id="Aff39"><label>39</label>Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ USA</aff><aff id="Aff40"><label>40</label>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany</aff><aff id="Aff41"><label>41</label>Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</aff><aff id="Aff42"><label>42</label>The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Coordinating center: Netherlands Cancer Institute, Amsterdam, The Netherlands</aff><aff id="Aff43"><label>43</label>N.N. Petrov Institute of Oncology, St.-Petersburg, 197758 Russia</aff><aff id="Aff44"><label>44</label>Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC USA</aff><aff id="Aff45"><label>45</label>Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Santariskiu st, Vilnius, Lithuania</aff><aff id="Aff46"><label>46</label>State Research Institute Centre for Innovative medicine, Zygymantu st. 9, Vilnius, Lithuania</aff><aff id="Aff47"><label>47</label>Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538 USA</aff><aff id="Aff48"><label>48</label>Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA USA</aff><aff id="Aff49"><label>49</label>Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia</aff><aff id="Aff50"><label>50</label>The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong</aff><aff id="Aff51"><label>51</label>Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong</aff><aff id="Aff52"><label>52</label>Unité de Prévention et d’Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France</aff><aff id="Aff53"><label>53</label>Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute) Catalan Institute of Oncology, Gran Via de l’Hospitalet, 199-203, 08908, L’Hospitalet Barcelona, Barcelona, Spain</aff><aff id="Aff54"><label>54</label>Department of Oncology, Lund University Hospital, Lund, Sweden</aff><aff id="Aff55"><label>55</label>Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy</aff><aff id="Aff56"><label>56</label>Familial Cancer Centre, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006 Australia</aff><aff id="Aff57"><label>57</label>Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052 Australia</aff><aff id="Aff58"><label>58</label>Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOC - IRCCS, Via Gattamelata 64, Padua, Italy</aff><aff id="Aff59"><label>59</label>Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA USA</aff><aff id="Aff60"><label>60</label>Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700, (Haartmaninkatu 8), 00029 HUS Helsinki, Finland</aff><aff id="Aff61"><label>61</label>Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany</aff><aff id="Aff62"><label>62</label>513 Parnassus Ave., HSE 901E, San Francisco, CA 94143-0794 USA</aff><aff id="Aff63"><label>63</label>Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10044 USA</aff><aff id="Aff64"><label>64</label>Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary</aff><aff id="Aff65"><label>65</label>5841 South Maryland Avenue, MC 2115 Chicago, IL USA</aff><aff id="Aff66"><label>66</label>Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 Korea</aff><aff id="Aff67"><label>67</label>NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY 14263 USA</aff><aff id="Aff68"><label>68</label>Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133 Milan, Italy</aff><aff id="Aff69"><label>69</label>Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria</aff><aff id="Aff70"><label>70</label>Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000 BE Amsterdam, The Netherlands</aff><aff id="Aff71"><label>71</label>Department of Medical Oncology, Family Cancer Clinic Erasmus University Medical Center Cancer institute, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands</aff><aff id="Aff72"><label>72</label>Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec Canada</aff><aff id="Aff73"><label>73</label>Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria</aff><aff id="Aff74"><label>74</label>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria Australia</aff><aff id="Aff75"><label>75</label>Service de Génétique Oncologique, Institut Curie, 26, rue d’Ulm, Paris, Cedex 05, France</aff><aff id="Aff76"><label>76</label>National Human Genome Research Institute, National Institutes of Health Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD 20892-8004 USA</aff><aff id="Aff77"><label>77</label>Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy</aff><aff id="Aff78"><label>78</label>Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal</aff><aff id="Aff79"><label>79</label>Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Malaysia</aff><aff id="Aff80"><label>80</label>University Malaya Cancer Research Institute, University Malaya, 50603 Kuala Lumpur, Malaysia</aff><aff id="Aff81"><label>81</label>Department of Epidemiology, Columbia University, New York, NY USA</aff><aff id="Aff82"><label>82</label>Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark</aff><aff id="Aff83"><label>83</label>Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia</aff><aff id="Aff84"><label>84</label>Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec Canada</aff><aff id="Aff85"><label>85</label>Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH USA</aff><aff id="Aff86"><label>86</label>Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 USA</aff><aff id="Aff87"><label>87</label>Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007 South Africa</aff><aff id="Aff88"><label>88</label>Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY USA</aff><aff id="Aff89"><label>89</label>Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany</aff><aff id="Aff90"><label>90</label>Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California 91010 USA</aff><aff id="Aff91"><label>91</label>Institute of Oncology, Rivka Ziv Medical Center, 13000 Zefat, Israel</aff><aff id="Aff92"><label>92</label>The Faculty of Medicine, Bar-Ilan University, Zefat, Israel</aff><aff id="Aff93"><label>93</label>4301 West Markham Street, Slot 793, Little Rock, AR 72205 USA</aff><aff id="Aff94"><label>94</label>Present Address: School of Women’s and Children’s Health, University of New South Wales and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010 Australia</aff></contrib-group><pub-date pub-type="epub"><day>11</day><month>11</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>11</day><month>11</month><year>2016</year></pub-date><pub-date pub-type="ppub"><year>2016</year></pub-date><volume>18</volume><elocation-id>112</elocation-id><history><date date-type="received"><day>12</day><month>4</month><year>2016</year></date><date date-type="accepted"><day>7</day><month>10</month><year>2016</year></date></history><permissions><copyright-statement>© The Author(s). 2016</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>Most <italic>BRCA1</italic> or <italic>BRCA2</italic> mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both <italic>BRCA1</italic> and <italic>BRCA2</italic> are rare, and the consequences of transheterozygosity are poorly understood.</p></sec><sec><title>Methods</title><p>From 32,295 female <italic>BRCA1/2</italic> mutation carriers, we identified 93 TH (0.3 %). “Cases” were defined as TH, and “controls” were single mutations at <italic>BRCA1</italic> (SH1) or <italic>BRCA2</italic> (SH2). Matched SH1 “controls” carried a BRCA1 mutation found in the TH “case”. Matched SH2 “controls” carried a BRCA2 mutation found in the TH “case”. After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.</p></sec><sec><title>Results</title><p>The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; <italic>p</italic> = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (<italic>p</italic> = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (<italic>p</italic> = 0.231), but was on average 4.5 years younger in TH than in SH2 (<italic>p</italic> < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (<italic>p</italic> = 0.010) or progesterone receptor (PR) positive (<italic>p</italic> = 0.013) than in SH1, but less likely to be ER positive (<italic>p</italic> < 0.001) or PR positive (<italic>p</italic> = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for <italic>BRCA1</italic> or <italic>BRCA2</italic> in either BC or OC.</p></sec><sec><title>Conclusions</title><p>Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s13058-016-0768-3) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Hereditary breast and ovarian cancer</kwd><kwd>Transheterozygosity</kwd><kwd>BRCA1</kwd><kwd>BRCA2</kwd></kwd-group><funding-group><award-group><funding-source><institution>Funding Sources are listed in the Appendix</institution></funding-source><award-id>See Appendix</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2016</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p>Women who have inherited mutations in <italic>BRCA1</italic> or <italic>BRCA2</italic> are at greatly increased risk of developing breast cancer (BC) and ovarian cancer (OC) [<xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR38">38</xref>]. Identification of a mutation at these loci can lead to risk or mortality reduction if optimal surveillance, risk-reducing mastectomy (RRM), and risk-reducing salpingo-oophorectomy (RRSO) are applied [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR29">29</xref>]. In addition, treatment of cancers in mutation carriers has advanced with the development of PARP inhibitors, which take advantage of the loss of <italic>BRCA1/2</italic> function in tumors [<xref ref-type="bibr" rid="CR37">37</xref>]. <italic>BRCA1</italic> and <italic>BRCA2</italic> are tumor suppressor genes, and tumors from the majority of mutation carriers have loss of heterozygosity (LOH), with loss of the normal allele, so there is no functioning protein [<xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR31">31</xref>]. In early studies, including a small number of tumor samples obtained from large BC and OC families, it was suggested that greater than 85 % of <italic>BRCA1-</italic> or <italic>BRCA2</italic>-associated cancers exhibited LOH, and all showed loss of the normal allele.</p><p>The vast majority of <italic>BRCA1</italic> and <italic>BRCA2</italic> mutation carriers are single heterozygotes for <italic>BRCA1</italic> (SH1) or <italic>BRCA2</italic> (SH2). Homozygosity of missense alleles at <italic>BRCA2</italic> (<italic>FANCD1</italic>) leads to Fanconi Anemia and increased cancer susceptibility, notably hematological malignancies [<xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR22">22</xref>]. At least three Fanconi Anemia cases are attributable to <italic>BRCA2/FANCD1</italic> homozygous mutations [<xref ref-type="bibr" rid="CR22">22</xref>]. Observations of homozygosity or compound heterozygosity at <italic>BRCA1</italic> are very rare. Domchek et al. [<xref ref-type="bibr" rid="CR9">9</xref>] reported a female patient with short stature, microcephaly, developmental delay, significant toxicity from chemotherapy, and epithelial ovarian carcinoma diagnosed at age 28 years. This woman was a compound heterozygote at <italic>BRCA1</italic>, with mutations c.2457delC (p.Asp821Ilefs*25) and c.5207 T > C (p.Val1736Ala). Both of these mutations are likely to be deleterious variants in <italic>BRCA1</italic>-associated cancer. The only other reported case of biallelic <italic>BRCA1</italic> mutations was in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23 [<xref ref-type="bibr" rid="CR30">30</xref>].</p><p>Transheterozygosity (TH) is the state of heterozygosity at two different loci. Here, we define TH to be inheritance of deleterious mutations in both <italic>BRCA1</italic> and <italic>BRCA2</italic>. Reports on several <italic>BRCA1/2</italic> transheterozygotes (TH) have been reported in the literature, mainly without further details on tumor or patient phenotype. Ramus et al. [<xref ref-type="bibr" rid="CR27">27</xref>] reported on one TH who had been diagnosed with both BC and OC, and was identified as having a mutation in <italic>BRCA1</italic> c.68_69delAG (185/187delAG) and <italic>BRCA2</italic> c.5946delT (6174delT). LOH in these tumors was not found. Additional reports identified TH for <italic>BRCA1</italic> c.2389G > T and <italic>BRCA2</italic> c.3068dupA [<xref ref-type="bibr" rid="CR21">21</xref>], <italic>BRCA1</italic> c.68_69delAG and a <italic>BRCA2</italic> c.5946delT [<xref ref-type="bibr" rid="CR36">36</xref>], and TH with <italic>BRCA1</italic> c.68_69delAG and <italic>BRCA2</italic> c.5946delT [<xref ref-type="bibr" rid="CR11">11</xref>] in four cases. In addition, a number of reports of TH with LOH in cancer samples have been published. Randall et al. [<xref ref-type="bibr" rid="CR28">28</xref>] reported one TH identified with a <italic>BRCA1</italic> c.3770_3771delGA and <italic>BRCA2</italic> c.5946delT, and being affected with both BC and OC. For the BC, only LOH at the <italic>BRCA1</italic> locus was found (not at <italic>BRCA2)</italic>, and the OC sustained LOH at both <italic>BRCA1</italic> and <italic>BRCA2</italic>. Tesoriero et al. [<xref ref-type="bibr" rid="CR35">35</xref>] reported a TH with <italic>BRCA1</italic> c.3770_3771delGA and <italic>BRCA2</italic> c.5946delT. The BC of this patient lost the wild-type <italic>BRCA2</italic> allele. Bell et al. [<xref ref-type="bibr" rid="CR1">1</xref>] reported on a TH with c.5266dupC <italic>BRCA1</italic> and c.5946delT <italic>BRCA2</italic> mutation having three independent BCs. They showed that LOH occurred in two <italic>BRCA2</italic> and one <italic>BRCA1</italic> tumor. A large clinic-based series of 1191 carriers from Israel [<xref ref-type="bibr" rid="CR20">20</xref>] identified 16 TH females, 14 with the c.68_69delAG <italic>BRCA1</italic> and c.5946delT <italic>BRCA2</italic> mutations and two with the c.5266dupC <italic>BRCA1</italic> and c.5946delT <italic>BRCA2</italic> mutations. A study from Germany identified eight female TH from 8162 BC/OC families and compared the clinical characteristics of the TH to their SH relatives and to SH in the family-based study [<xref ref-type="bibr" rid="CR14">14</xref>].</p><p>To characterize the nature of TH and clinical phenotypes of TH, we used the Consortium of Investigators of Modifiers of <italic>BRCA1/2</italic> (CIMBA) dataset of 32,295 female <italic>BRCA1/2</italic> mutation carriers ascertained in high-risk clinics and population-based studies. From this dataset, we investigated the occurrence of TH, we compared the characteristics and features of BC and OC in TH and single <italic>BRCA1</italic> or <italic>BRCA2</italic> mutations, and we examined LOH in as many cancer samples as possible.</p></sec><sec id="Sec2"><title>Methods</title><sec id="Sec3"><title>Study sample</title><p>Details of CIMBA participating centers and data collection have been reported previously [<xref ref-type="bibr" rid="CR5">5</xref>]. All the included mutation carriers participated in clinical and research studies at the host institutions after providing informed consent under IRB-approved protocols. Fifty-five centers and multicenter consortia (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S1) submitted data that met the CIMBA inclusion criteria [<xref ref-type="bibr" rid="CR5">5</xref>]. Only female carriers with pathogenic <italic>BRCA1/2</italic> mutations, concerning TH, SH1, and SH2 mutation carriers, were included in the current analysis. Pathogenicity of mutation was defined as follows: 1) generating a premature termination codon (PTC), except variants generating a PTC in exon 27 after codon 3010 of <italic>BRCA2</italic>; 2) large in-frame deletions that span one or more exons; and 3) deletion of transcription regulatory regions (promoter and/or first exon) expected to cause lack of expression of mutant allele. We also included missense variants considered pathogenic by using multifactorial likelihood approaches [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR12">12</xref>]. Mutations that did not meet the above criteria but have been classified as pathogenic by Myriad Genetics, Inc. (Salt Lake City, UT, USA) were also included.</p><p>Mutations are described using the Human Genome Variation Society (HGVS) nomenclature (<ext-link ext-link-type="uri" xlink:href="http://www.HGVS.org/varnomen">http://www.HGVS.org/varnomen</ext-link>) where the nucleotide numbering is from the A of the ATG translation initiator codon. For deletions or insertions, the most 3′ position possible was arbitrarily assigned as the altered nucleotide. The description of mutations of all types is given at the genomic level (using cDNA reference sequences NM_007294.3/<italic>BRCA1</italic> and NM_000059/<italic>BRCA2</italic>). BIC nomenclature was also presented for common variants that are familiar to many researchers and clinicians by their BIC designation (<ext-link ext-link-type="uri" xlink:href="http://research.nhgri.nih.gov/bic">http://research.nhgri.nih.gov/bic</ext-link>). For BIC nomenclature, cDNA sequences were used as reference sequence (Genbank: U14680/<italic>BRCA1</italic> and NM_000059.1/<italic>BRCA2</italic>). The nucleotide numbering is from nucleotide 1 of the cDNA gene sequence and for deletions or insertions the most 3′ position possible was arbitrarily assigned as the altered nucleotide.</p><p>In order to compare the TH with SH1 and SH2 mutation carriers on phenotypes of interest, we created a matched case–control set, in which “cases” were defined as TH, and “controls” were SH1 and SH2 mutation carriers. Matched SH1 “controls” carried a BRCA1 mutation found in the TH “case”. Matched SH2 “controls” carried a BRCA2 mutation found in the TH “case”. SH1 and SH2 were not matched to TH for any other characteristics. Using this approach, we identified 91 TH and 9316 matched SH1 mutation carriers, and 89 TH and 3370 matched SH2 mutation carriers.</p></sec><sec id="Sec4"><title>Loss of heterozygosity</title><p>From 10 TH individuals, tumor tissue was available from twelve tumors, and blood DNA from 10 TH. From one case, tumor tissue from both BC and OC was available, and from another case affected with bilateral BC, tumor samples were available from both breast tumors. Hematoxylin and eosin (H&E) slides from each tumor were examined by a specialist pathologist. Areas of >80 % tumor cells were marked for macro-dissection. DNA from two 10-micron unstained slides was extracted using the Qiagen QIAmp DNA FFPE Tissue Kit using the standard protocol but with 500 μl deparaffinization solution.</p><p>We performed micro-satellite analysis to objectively detect LOH as described previously [<xref ref-type="bibr" rid="CR16">16</xref>]. We amplified patient tumor and blood DNA for two markers within <italic>BRCA1</italic> (D17S855 and D17S1322) and four markers around <italic>BRCA2</italic> (D13S290, D13S260, D13S1698, and D13S171). The heterozygosity for these markers ranged from 0.46 to 0.82 [<xref ref-type="bibr" rid="CR17">17</xref>, <xref ref-type="bibr" rid="CR26">26</xref>]. Primer sequences and distance from <italic>BRCA1</italic> or <italic>BRCA2</italic> are given in Additional file <xref rid="MOESM1" ref-type="media">1</xref> (Table S2). After polymerase chain reaction (PCR) amplification, samples were size-separated on a 96 capillary DNA analyzer (Applied Biosystems 3730xl). Data were analyzed using Genemapper Software (Applied Biosystems). For micro-satellites that were heterozygous, the ratios of allele peak heights for each tumor sample were compared to the allele peak heights for the blood DNA sample using the following formula L = (at2 X an1)/(at1 X an2), where L = the ratio; a = the height of the peak; n1 and n2 = normal allele 1 and normal allele 2; t1 and t2 = tumor allele 1 and tumor allele 2. All ten cases were informative for at least one marker in <italic>BRCA1</italic>. Where cases were informative for both markers, the LOH data were consistent for the two nearby markers. All ten cases were also informative for at least one of the four markers in <italic>BRCA2</italic>. In two cases, the data were not consistent across all markers in the 1.74 MB region and the data for the marker closest to <italic>BRCA2</italic> was used.</p><p>To complement the information obtained from micro-satellite analysis, we also undertook DNA sequence analysis. For each individual, a small region (<200 bp) around each of their two mutations was PCR-amplified from both tumor and blood DNA. DNA from peripheral blood of a healthy control individual was also amplified for each fragment as a control for no mutation. We used 10 ng of DNA in the PCR reaction, using standard protocol and primer sequences (given in Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S3). All three samples for each mutation were then treated with EXO-SAP-IT (Affymetrix) and Sanger sequenced using standard methods [<xref ref-type="bibr" rid="CR32">32</xref>]. This sequencing was used to confirm the presence of each mutation in the blood DNA from the patient and not in the control sample. We also assessed the mutation status in the tumor to determine if LOH had occurred. Since we extracted areas of >80 % tumor cells, both alleles can be present even when LOH is present, due to contaminating normal tissue. Therefore, for each tumor we determined for each mutation if the two alleles were at an equal ratio compared to the germline sample or if there was a decrease in one of the two alleles.</p></sec><sec id="Sec5"><title>Statistical Analysis</title><p>For comparison of TH and SH mutation carriers, contingency table analysis using a chi-square test was used for dichotomous variables, and a <italic>t</italic> test for continuous variables. Fisher’s exact tests were used if sample sizes in any contingency table cell were less than five. Analyses were done in STATA, v. 13.1.</p></sec></sec><sec id="Sec6"><title>Results</title><sec id="Sec7"><title>Characteristics of TH versus SH1 and SH2 mutation carriers</title><p>Table <xref rid="Tab1" ref-type="table">1</xref> describes the 93 female TH from 84 families identified from the CIMBA database. Among the matched TH-SH1/SH2 sets, 25 had no cancer diagnosis. The average age of these women was 39 years and the average age at diagnosis of BC was 41 years. Only 16 women were less than age 41 and 9 women were over age 41 at the time of diagnosis (mean age 49.9, range 41.4–67.9). Table <xref rid="Tab2" ref-type="table">2</xref> shows that OC age for the matched BRCA1 TH cases was 51.1 years and SH1 controls was 50.9 years (<italic>p</italic> = 0.154). For the matched BRCA2 set the average OC age for the TH cases was 54.7 years and for SH2 controls was 56.8 years (<italic>p</italic> = 0.421) (Fig. <xref rid="Fig1" ref-type="fig">1</xref>).<table-wrap id="Tab1"><label>Table 1</label><caption><p>Transheterozygote <italic>BRCA1 + BRCA2</italic> mutations in 93 women</p></caption><table frame="hsides" rules="groups"><thead><tr><th><italic>BRCA1</italic> mutation</th><th><italic>BRCA2</italic> mutation</th><th rowspan="3"><italic>N</italic></th><th rowspan="3">%</th><th rowspan="2" colspan="2">Breast cancer only</th><th rowspan="2" colspan="2">Ovarian cancer only</th><th rowspan="2" colspan="2">Breast + ovarian cancer</th><th rowspan="2" colspan="2">No cancer</th><th rowspan="3">Self-identified race/ethnicity</th><th rowspan="3">Country of ascertainment</th></tr><tr><th rowspan="2">HGVS: genomic level</th><th rowspan="2">HGVS: genomic level</th></tr><tr><th><italic>n</italic></th><th>%</th><th><italic>n</italic></th><th>%</th><th><italic>n</italic></th><th>%</th><th><italic>n</italic></th><th>%</th></tr></thead><tbody><tr><td>c.-19-?_80 + ?dup</td><td>c.8633-?_8754 + ?amp*</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Jewish</td><td>Hungary</td></tr><tr><td>c.68_69delAG</td><td>c.5946delT</td><td>31</td><td>33.3</td><td>13</td><td>13.9</td><td>1</td><td>1.1</td><td>3</td><td>3.2</td><td>14</td><td>15.0</td><td>Caucasian, Jewish, NR</td><td>USA, Hungary, Israel</td></tr><tr><td>c.68_69delAG</td><td>c.5722_5723delCT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.1016delA</td><td>c.7379_7382delACAA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Asian</td><td>USA</td></tr><tr><td>c.1390delA*</td><td>c.658_659delGT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Hispanic</td><td>USA</td></tr><tr><td>c.1504_1508del5</td><td>c.2798_2799delCA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Asian</td><td>Korea</td></tr><tr><td>c.1504_1508del5</td><td>c.462_463delAA</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.1687C > T</td><td>c.6469C > T</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Italy</td></tr><tr><td>c.1793 T > ?</td><td>c.8537_8538delAG</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>USA</td></tr><tr><td>c.181 T > G</td><td>c.1318_1319dupCT</td><td>3</td><td>3.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>2</td><td>2.2</td><td>Caucasian</td><td>Austria</td></tr><tr><td>c.211A > G</td><td>c.4380_4381delTT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>UK</td></tr><tr><td>c.212 + 1G > A</td><td>c.739_740delAT*</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Spain</td></tr><tr><td>c.213-12A > G</td><td>c.7180A > T</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Italy</td></tr><tr><td>c.2389G > T</td><td>c.3068dupA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Canada</td></tr><tr><td>c.2405_2406delTG</td><td>c.4284dupT</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Italy</td></tr><tr><td>c.246delT</td><td>c.517-2A > G</td><td>2</td><td>2.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>Caucasian</td><td>UK</td></tr><tr><td>c.301 + 1G > A</td><td>c.5682C > G</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>USA</td></tr><tr><td>c.3048_3052dup5</td><td>c.2830A > T</td><td>2</td><td>2.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>NR</td><td>Sweden</td></tr><tr><td>c.3155delA</td><td>c.3160_ 3163delGATA</td><td>2</td><td>2.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>Caucasian</td><td>Australia</td></tr><tr><td>c.3196G > T*</td><td>c.658_659delGT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.3228_3229delAG</td><td>c.3689delC</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>Caucasian</td><td>UK</td></tr><tr><td>c.3228_3229delAG</td><td>c.9253dupA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Italy</td></tr><tr><td>c.3400G > T</td><td>c.2808_2811delACAA</td><td>2</td><td>2.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>Caucasian</td><td>UK</td></tr><tr><td>c.3477_3480 delAAAG</td><td>c.9401delG</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Italy</td></tr><tr><td>c.3627dupA</td><td>c.6724_6725delGA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Asian</td><td>Korea</td></tr><tr><td>c.3700_3704del5</td><td>c.681 + 1G > A</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Australia</td></tr><tr><td>c.3700_3704del5</td><td>c.1815dupA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.3756_3759delGTCT</td><td>c.7757G > A</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>USA</td></tr><tr><td>c.3759_3760delTA</td><td>c.9699_9702 delTATG</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Hispanic</td><td>USA</td></tr><tr><td>c.3770_3771delAG</td><td>c.5946delT</td><td>2</td><td>2.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>NR, Jewish</td><td>Australia, USA</td></tr><tr><td>c.3839_3843 delinsAGGC</td><td>c.1636delT</td><td>2</td><td>2.2</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>NR</td><td>France</td></tr><tr><td>c.390C > A</td><td>c.3018delA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Asian</td><td>Korea</td></tr><tr><td>3910delG</td><td>c.2830A > T</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.3916_3917delTT</td><td>c.5380delG*</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Italy</td></tr><tr><td>c.4035delA</td><td>c.658_659delGT</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>Caucasian</td><td>Australia</td></tr><tr><td>c.4065_4068delTCAA</td><td>c.5350_5351delAA</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>USA</td></tr><tr><td>c.4186-?_4357 + ?dup</td><td>c.2636_2637delCT</td><td>2</td><td>2.2</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>Caucasian</td><td>UK</td></tr><tr><td>c.427G > T</td><td>c.8730delT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Denmark</td></tr><tr><td>c.5030_5033 delCTAA</td><td>c.1399A > T</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Asian</td><td>Korea</td></tr><tr><td>c.5123C > A</td><td>c.6275_6276delTT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.5136G > A</td><td>c.4965delC</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Asian</td><td>USA</td></tr><tr><td>c.5193 + 1delG</td><td>c.658_659delGT</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.5251C > T</td><td>c.6753_6754delTT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Austria</td></tr><tr><td>c.5266dupC</td><td>c.8364G > A</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Austria</td></tr><tr><td>c.5266dupC</td><td>c.5946delT</td><td>5</td><td>5.4</td><td>3</td><td>3.2</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>Jewish</td><td>UK, Israel</td></tr><tr><td>c.5266dupC</td><td>c.4478_4481delAAAG</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.5266dupC</td><td>c.5645C > A</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.5406 + 664_*8273del</td><td>c.9748dupT</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Greece</td></tr><tr><td>c.548-?_4185 + ?del</td><td>c.2269A > T*</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>c.962G > A</td><td>c.2231C > G</td><td>1</td><td>1.1</td><td>1</td><td>1.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>Caucasian</td><td>Germany</td></tr><tr><td>Total</td><td></td><td>93</td><td>100</td><td>51</td><td>54.8</td><td>4</td><td>4.3</td><td>13</td><td>14.0</td><td>25</td><td>26.9</td><td></td><td></td></tr><tr><td>Mean age (range)</td><td></td><td></td><td></td><td colspan="2">39.9 (23–67)</td><td colspan="2">59.2 (57–62)</td><td colspan="2">41.9 (26–53)</td><td colspan="2">39.1 (20–68)</td><td></td><td></td></tr></tbody></table><table-wrap-foot><p>*Not included in the matched analysis because one of the mutations found in the TH was not found among the SH1/SH2 carriers</p><p><italic>HGVS</italic> Human Genome Variation Society, <italic>NR</italic> not reported</p></table-wrap-foot></table-wrap><table-wrap id="Tab2"><label>Table 2</label><caption><p>Description of <italic>BRCA1, BRCA2</italic>, and transheterozygote <italic>BRCA1 + BRCA2</italic> mutation carriers</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Variable</th><th>Value</th><th><italic>BRCA1 + BRCA2 (TH)N(%)</italic></th><th><italic>BRCA1 (SH1)N(%)</italic></th><th><italic>P</italic> value*</th><th><italic>P</italic> value*</th><th><italic>BRCA1</italic> + <italic>BRCA2 (TH) N(%)</italic></th><th><italic>BRCA2 (SH2)N(%)</italic></th><th><italic>P</italic> value**</th><th><italic>P</italic> value**</th></tr></thead><tbody><tr><td>Total matched</td><td></td><td>91</td><td>9316</td><td></td><td></td><td>89</td><td>3370</td><td></td><td></td></tr><tr><td>Year of birth</td><td><1940<break></break>1941–1950<break></break>1951–1960<break></break>1961–1970<break></break>>1970</td><td>5 (5.5)<break></break>20 (22.0)<break></break>21 (22.6)<break></break>27 (29.0)<break></break>18 (19.8)</td><td>886 (9.5)<break></break>1628 (17.4)<break></break>2607 (28.0)<break></break>2409 (25.9)<break></break>1779 (19.0)</td><td>0.424</td><td>(ref)<break></break>0.112<break></break>0.474<break></break>0.153<break></break>0.245</td><td>5 (5.6)<break></break>19 (21.3)<break></break>19 (21.3)<break></break>27 (30.3)<break></break>19 (21.3)</td><td>486 (14.4)<break></break>735 (21.8)<break></break>914 (27.1)<break></break>724 (21.5)<break></break>511 (15.2)</td><td><bold>0.025</bold></td><td>(ref)<break></break>0.060<break></break>0.156<break></break><bold>0.005</bold><break></break><bold>0.007</bold></td></tr><tr><td>Ethnicity</td><td>White<break></break>African American<break></break>Asian<break></break>Hispanic<break></break>Jewish<break></break>Other</td><td>47 (51.6)<break></break>0 (0)<break></break>6 (6.6)<break></break>1 (1.1)<break></break>30 (33.0)<break></break>7 (7.7)</td><td>5736 (61.6)<break></break>20 (0.2)<break></break>82 (0.9)<break></break>143 (1.5)<break></break>1779 (19.1)<break></break>1556 (16.7)</td><td><bold><0.001</bold></td><td>(ref)<break></break>1.00*<break></break><bold><0.001</bold><break></break>1.00<break></break><bold>0.002</bold><break></break>--</td><td>45 (50.6)<break></break>0 (0)<break></break>6 (6.7)<break></break>2 (2.2)<break></break>29 (32.6)<break></break>7 (7.9)</td><td>1686 (50.0)<break></break>15 (0.4)<break></break>66 (2.0)<break></break>57 (1.7)<break></break>936 (27.8)<break></break>610 (18.1)</td><td><bold>0.007</bold></td><td>(ref)<break></break>1.00*<break></break><bold>0.004</bold><break></break>0.667<break></break>0.573<break></break><bold>--</bold></td></tr><tr><td>Breast cancer</td><td>No<break></break>Yes</td><td>29 (31.9)<break></break>62 (68.1)</td><td>4470 (48.0)<break></break>4846 (52.0)</td><td><bold>0.002</bold></td><td></td><td>29 (32.6)<break></break>60 (67.4)</td><td>1671 (49.6)<break></break>1699 (50.4)</td><td><bold>0.002</bold></td><td></td></tr><tr><td>Age of breast cancer</td><td>Mean (range)</td><td>40.4 (23–67)</td><td>41.9 (18–82)</td><td>0.231</td><td></td><td>40.5 (23–67)</td><td>45.0 (19–82)</td><td><bold><0.001</bold></td><td></td></tr><tr><td>Ovarian cancer</td><td>No<break></break>Yes</td><td>74 (81.3)<break></break>17 (18.7)</td><td>7766 (83.4)<break></break>1550 (16.6)</td><td>0.603</td><td></td><td>74 (83.1)<break></break>15 (16.9)</td><td>3056 (90.7)<break></break>314 (9.3)</td><td><bold>0.017</bold></td><td></td></tr><tr><td>Age of ovarian cancer</td><td>Mean (range)</td><td>54.1 (36–66)</td><td>50.9 (20–85)</td><td>0.154</td><td></td><td>54.7 (42–66)</td><td>56.8 (26–89)</td><td>0.421</td><td></td></tr><tr><td>Bilateral mastectomy</td><td>No<break></break>Yes</td><td>58 (63.7)<break></break>8 (9.0)</td><td>4807 (51.6)<break></break>809 (8.7)</td><td>0.599</td><td></td><td>58 (65.2)<break></break>8 (9.0)</td><td>1856 (55.0)<break></break>305 (9.1)</td><td>0.646</td><td></td></tr><tr><td>Prophylactic oophorectomy</td><td>No<break></break>Yes</td><td>45 (49.5)<break></break>24 (26.4))</td><td>3583 (38.4)<break></break>2476 (26.6)</td><td>0.307</td><td></td><td>45 (50.6)<break></break>24 (27.0)</td><td>1388 (41.2)<break></break>980 (29.1)</td><td>0.272</td><td></td></tr><tr><td>Follow up age (if no cancer)</td><td>Mean (range)</td><td>39.1 (20–68)</td><td>40.5 (18–99)</td><td>0.587</td><td></td><td>39.1 (20–68)</td><td>44.1 (18–94)</td><td>0.068</td><td></td></tr></tbody></table><table-wrap-foot><p>*Matched <italic>BRCA1</italic> mutation carriers vs <italic>BRCA1 + BRCA2</italic> mutation carriers; **matched <italic>BRCA2</italic> mutation carriers vs <italic>BRCA1 + BRCA2</italic> mutation carriers</p><p>Significant <italic>p</italic> values are shown in bold type</p></table-wrap-foot></table-wrap><fig id="Fig1"><label>Fig. 1</label><caption><p>Age of breast and ovarian cancer diagnosis by mutation status</p></caption><graphic xlink:href="13058_2016_768_Fig1_HTML" id="MO1"></graphic></fig></p><p>The most common TH involved inheritance of two of the three common Jewish mutations: 5 (5.4 %) women inherited <italic>BRCA1</italic> c.5266dupC and <italic>BRCA2</italic> c.5946delT; 31 (33.3 %) women inherited <italic>BRCA1</italic> c.68_69delAG and <italic>BRCA2</italic> c.5946delT. Six (6.5 %) women carried one of the three common Jewish mutations and another mutation. The majority of the remaining TH were observed only once. The majority of the TH self-identified as non-Hispanic Caucasian or Jewish. Of the 6907 women who carried one of the Jewish founder mutations, 2732 (39.6 %) self-identified as Jewish, 947 (13.7 %) were unknown, and 3225 (46.7 %) reported an ethnicity other than Jewish. We observed two TH in Hispanics and six TH in Asians (four of which were Korean). Of the 93 TH, 51 were diagnosed with BC only, 4 with OC only, 13 with both BC and OC, and 25 with no cancer diagnosis.</p><p>The matched datasets included 91 TH and 9316 SH1 for the <italic>BRCA1</italic> matched analysis, and 89 TH and 3370 SH2 for the <italic>BRCA2</italic> matched analysis. Two <italic>BRCA1</italic> mutations were observed among the TH in our dataset that were not observed among SH1 (c.1390delA and c.3196G > T), and four <italic>BRCA2</italic> mutations were observed in the TH dataset that were not observed among the SH2 (c.8633-?_8754 + ?amp, c.739_740delAT, c.5380delG, and c.2269A > T). These six carriers were not included in the analysis (denoted by asterisk in Table <xref rid="Tab1" ref-type="table">1</xref>). TH were more likely to be born more recently (i.e., since 1961) than SH2 mutation carriers but not when compared to SH1s (Table <xref rid="Tab2" ref-type="table">2</xref>). The TH group consisted of more individuals from Asian ancestry compared to the SH1 and SH2 groups, with an excess of women having a Jewish ancestry vs. the SH1 group. TH were more likely to have ever been diagnosed with BC than SH1 or SH2 individuals (68.1 % vs. 52.0 %; <italic>p</italic> = 0.002, and 67.4 % vs. 50.4 %; <italic>p</italic> = 0.002), and TH were more likely to be diagnosed with OC than SH2 women (16.9 % vs. 9.3 %; <italic>p</italic> = 0.017), which was not observed in TH vs. SH1 women, perhaps due to the lower incidence of OC in <italic>BRCA2</italic> vs. <italic>BRCA1</italic>. Age at BC diagnosis was significantly different for TH vs. SH2 (40.5 years vs. 45.0 years; <italic>p</italic> < 0.001), but there was no difference between TH and SH1.</p><p>There were 64 TH cases with BC. Of these, 62 TH were matched to 4846 SH1s and 60 TH were matched to 1699 SH2 (Table <xref rid="Tab3" ref-type="table">3</xref>). TH were more likely to have estrogen receptor (ER)- and progesterone receptor (PR)-positive BC than SH1s (ER: 42.9 % vs. 24.0 %; <italic>p</italic> = 0.010; PR: 40.6 % vs. 20.0 %; <italic>p</italic> = 0.013). In contrast, the BCs of TH were less likely ER- and PR-positive than in SH2s (ER: 42.9 % vs. 76.5 %; <italic>p</italic> < 0.0001; PR: 40.6 % vs. 62.8 %; <italic>p</italic> = 0.012). The proportion of ER- and PR-positive BCs in TH was intermediate to that of SH1 and SH2. No difference was seen regarding the HER2 status between the BCs of TH and SH1s and SH2s, respectively, although the available numbers were small. No differences in other BC characteristics (morphology, grade, stage) were observed.<table-wrap id="Tab3"><label>Table 3</label><caption><p>Breast tumor characteristics of <italic>BRCA1, BRCA2,</italic> and transheterozygote <italic>BRCA1 + BRCA2</italic> mutation carriers</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Trait</th><th>Value</th><th><italic>BRCA1 + BRCA2 (TH) N(%)</italic></th><th><italic>BRCA1 (SH1) N(%)</italic></th><th><italic>P</italic> value</th><th><italic>BRCA1 + BRCA2 (TH) N(%)</italic></th><th><italic>BRCA2 (SH2) N(%)</italic></th><th><italic>P</italic> value</th></tr></thead><tbody><tr><td><italic>N</italic></td><td></td><td>62</td><td>4846</td><td></td><td>60</td><td>1699</td><td></td></tr><tr><td rowspan="2">HER2</td><td>Negative</td><td>14 (93.3)</td><td>908 (88.7)</td><td>1.00</td><td>15 (93.8)</td><td>274 (86.2)</td><td>0.706</td></tr><tr><td>Positive</td><td>1 (7.7)</td><td>116 (11.3)</td><td></td><td>1 (6.3)</td><td>44 (13.8)</td><td></td></tr><tr><td rowspan="2">PR</td><td>Negative</td><td>19 (59.4)</td><td>1260 (80.0)</td><td><bold>0.013</bold></td><td>19 (59.4)</td><td>215 (37.2)</td><td><bold>0.012</bold></td></tr><tr><td>Positive</td><td>13 (40.6)</td><td>356 (20.0)</td><td></td><td>13 (40.6)</td><td>363 (62.8)</td><td></td></tr><tr><td rowspan="2">ER</td><td>Negative</td><td>20 (57.1)</td><td>1347 (76.0)</td><td><bold>0.010</bold></td><td>20 (57.1)</td><td>150 (23.5)</td><td><bold><0.0001</bold></td></tr><tr><td>Positive</td><td>15 (42.9)</td><td>424 (24.0)</td><td></td><td>15 (42.9)</td><td>487 (76.5)</td><td></td></tr><tr><td rowspan="2">Nodal status</td><td>Negative</td><td>20 (66.7)</td><td>1197 (65.1)</td><td>0.854</td><td>19 (65.5)</td><td>399 (61.3)</td><td>0.647</td></tr><tr><td>Positive</td><td>10 (33.3)</td><td>643 (35.0)</td><td></td><td>10 (34.5)</td><td>252 (38.7)</td><td></td></tr><tr><td rowspan="3">Grade</td><td>Well differentiated</td><td>2 (7.1)</td><td>36 (2.3)</td><td>0.161</td><td>2 (7.1)</td><td>36 (6.4)</td><td>0.690</td></tr><tr><td>Moderately differentiated</td><td>8 (28.8)</td><td>342 (22.1)</td><td></td><td>8 (28.8)</td><td>207 (36.6)</td><td></td></tr><tr><td>Poorly/undifferentiated</td><td>18 (64.3)</td><td>1172 (75.6)</td><td></td><td>18 (64.3)</td><td>322 (57.0)</td><td></td></tr><tr><td rowspan="5">Stage</td><td>0</td><td>1 (4.8)</td><td>34 (3.6)</td><td>0.541</td><td>1 (4.6)</td><td>48 (13.9)</td><td>0.065</td></tr><tr><td>1</td><td>7 (33.3)</td><td>399 (42.2)</td><td></td><td>7 (31.8)</td><td>123 (35.7)</td><td></td></tr><tr><td>2</td><td>13 (61.9)</td><td>440 (46.6)</td><td></td><td>14 (63.6)</td><td>124 (35.9)</td><td></td></tr><tr><td>3</td><td>0 (0)</td><td>65 (6.9)</td><td></td><td>0 (0)</td><td>36 (10.4)</td><td></td></tr><tr><td>4</td><td>0 (0)</td><td>7 (0.7)</td><td></td><td>0 (0)</td><td>14 (4.1)</td><td></td></tr><tr><td rowspan="4">Morphology</td><td>Ductal</td><td>26 (70.3)</td><td>1544 (74.3)</td><td>0.345</td><td>27 (73.0)</td><td>629 (78.8)</td><td>0.359</td></tr><tr><td>Lobular</td><td>3 (8.1)</td><td>61 (2.9)</td><td></td><td>3 (8.1)</td><td>70 (8.8)</td><td></td></tr><tr><td>Medullary</td><td>3 (8.1)</td><td>173 (8.3)</td><td></td><td>2 (5.4)</td><td>13 (1.6)</td><td></td></tr><tr><td>Other</td><td>5 (13.5)</td><td>301 (14.5)</td><td></td><td>5 (13.5)</td><td>86 (10.8)</td><td></td></tr><tr><td>Number of positive nodes (SD)</td><td></td><td>2 (6.1)</td><td>1.2 (3.4)</td><td>0.215</td><td>2.1 (6.2)</td><td>1.7 (3.9)</td><td>0.627</td></tr><tr><td>Tumor size (SD)</td><td></td><td>19.0 (14.9)</td><td>18.3 (12.5)</td><td>0.775</td><td>19.0 (14.9)</td><td>19.2 (14.6)</td><td>0.932</td></tr></tbody></table><table-wrap-foot><p>Significant <italic>p</italic> values are shown in bold type</p><p><italic>ER</italic> estrogen receptor, <italic>PR</italic> progesterone receptor, <italic>SD</italic> standard deviation</p></table-wrap-foot></table-wrap></p><p>Only 17 TH were diagnosed with OC, and thus we had limited data on features of OC to make inferences regarding differences in TH compared with SH1 or SH2. No statistically significant differences were observed for OC traits between TH and SHs (Table <xref rid="Tab4" ref-type="table">4</xref>). Surprisingly, four borderline tumors were reported in both the SH1 and SH2 groups.<table-wrap id="Tab4"><label>Table 4</label><caption><p>Ovarian tumor characteristics of <italic>BRCA1, BRCA2,</italic> and transheterozygote <italic>BRCA1 + BRCA2</italic> mutation carriers</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Trait</th><th>Value</th><th><italic>BRCA1 + BRCA2 (TH)N(%)</italic></th><th><italic>BRCA1 (SH1)N(%)</italic></th><th><italic>P</italic> value</th><th><italic>BRCA1 + BRCA2 (TH)N(%)</italic></th><th><italic>BRCA2 (SH2)N(%)</italic></th><th><italic>P</italic> value</th></tr></thead><tbody><tr><td><italic>N</italic></td><td></td><td>17</td><td>1550</td><td></td><td>15</td><td>314</td><td></td></tr><tr><td rowspan="3">Grade</td><td>Well differentiated</td><td>0</td><td>8 (2.8)</td><td>0.930</td><td>0</td><td>4 (6.2)</td><td>0.847</td></tr><tr><td>Moderately differentiated</td><td>1 (25)</td><td>60 (20.8)</td><td></td><td>1 (25)</td><td>12 (18.5)</td><td></td></tr><tr><td>Poorly/undifferentiated</td><td>3 (75)</td><td>220 (76.4)</td><td></td><td>3 (75)</td><td>49 (75.4)</td><td></td></tr><tr><td rowspan="4">Stage</td><td>1</td><td>0</td><td>39 (17.4)</td><td>0.600</td><td>0</td><td>6 (13.3)</td><td>0.589</td></tr><tr><td>2</td><td>1 (33.3)</td><td>31 (13.8)</td><td></td><td>1 (33.3)</td><td>5 (11.1)</td><td></td></tr><tr><td>3</td><td>2 (66.7)</td><td>120 (53.6)</td><td></td><td>2 (66.7)</td><td>28 (62.2)</td><td></td></tr><tr><td>4</td><td>0</td><td>34 (15.2)</td><td></td><td>0</td><td>6 (13.3)</td><td></td></tr><tr><td rowspan="5">Morphology</td><td>Serous</td><td>5 (83.3)</td><td>292 (66.8)</td><td>0.905</td><td>5 (83.3)</td><td>71 (73.2)</td><td>0.943</td></tr><tr><td>Mucinous</td><td>0</td><td>4 (0.9)</td><td></td><td>0</td><td>2 (2.0)</td><td></td></tr><tr><td>Endometroid</td><td>0</td><td>44 (10.1)</td><td></td><td>0</td><td>7 (7.2)</td><td></td></tr><tr><td>Clear cell</td><td>0</td><td>6 (1.4)</td><td></td><td>0</td><td>2 (2.0)</td><td></td></tr><tr><td>Other</td><td>1 (16.7)</td><td>91 (20.8)</td><td></td><td>1 (16.7)</td><td>15 (15.5)</td><td></td></tr><tr><td rowspan="2">Behavior</td><td>Invasive</td><td>7 (100)</td><td>449 (99.1)</td><td>0.803</td><td>6 (100)</td><td>89 (95.7)</td><td>0.604</td></tr><tr><td>Borderline</td><td>0</td><td>4 (0.9)</td><td></td><td>0</td><td>4 (4.3)</td><td></td></tr></tbody></table></table-wrap></p></sec><sec id="Sec8"><title>Loss of heterozygosity</title><p>Due to the frequent LOH in SH individuals, we examined the hypothesis that either <italic>BRCA1</italic> or <italic>BRCA2</italic> would be lost in each of the TH individuals due to LOH, and that whichever gene was lost could have an impact on their tumor characteristics. Of the 68 TH individuals with cancer, LOH analysis of three tumors from two cases had previously been published by our group using the same methods as the newly identified cases [<xref ref-type="bibr" rid="CR27">27</xref>]. In the context of the current study, 12 additional tumor samples from 10 patients were analyzed (Table <xref rid="Tab5" ref-type="table">5</xref>). We first used micro-satellite markers and an objective ratio of peak heights to determine if there was loss of one of the alleles when an individual was heterozygous [<xref ref-type="bibr" rid="CR3">3</xref>] (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Tables S4 and S5). LOH analysis with micro-satellite markers normally includes linkage or segregation data to determine if the normal allele is lost. Since we did not have samples from other family members, we performed Sanger sequencing at the position of the mutations in both germline and tumor samples to determine which allele was lost. One sample failed for the sequencing so it was not possible to determine whether the normal or mutated allele was lost. Some samples showed loss of the mutant allele, which would suggest random loss. Tumors that exhibited LOH by micro-satellite analysis but did not indicate a decrease of the normal allele by sequencing were not considered to exhibit classic LOH. Following both sets of analyses and including our previously published data, one breast tumor (case 8) and one OC (case 2) showed LOH for <italic>BRCA1</italic>, two breast tumors (cases 9 and 11) showed LOH of <italic>BRCA2</italic>, and the remaining tumors provided no evidence for LOH at either <italic>BRCA1</italic> or <italic>BRCA2</italic> (Table <xref rid="Tab5" ref-type="table">5</xref>).<table-wrap id="Tab5"><label>Table 5</label><caption><p>Loss of heterozygosity in tumor tissue</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="5"></th><th colspan="3">LOH in breast tumor</th><th colspan="3">LOH in ovarian tumor</th></tr><tr><th>Case</th><th>Diagnosis</th><th>Tissue studied</th><th><italic>BRCA1</italic> mutation</th><th><italic>BRCA2</italic> mutation</th><th>Micro-satellite Data</th><th>Sequence data</th><th>Inference</th><th>Micro-satellite data</th><th>Sequence data</th><th>Inference</th></tr></thead><tbody><tr><td>1</td><td>DCIS</td><td>DCIS</td><td>c.5136G > A</td><td>c.4965delC</td><td><italic>BRCA1, BRCA2</italic></td><td>No</td><td>No LOH</td><td></td><td></td><td></td></tr><tr><td>2</td><td>Breast</td><td>Inv Br</td><td>c.1793 T > A</td><td>c.8537_8538delAG</td><td><italic>BRCA2</italic></td><td><italic>BRCA1</italic></td><td>No LOH</td><td></td><td></td><td></td></tr><tr><td>3</td><td>Invasive breast</td><td>Inv Br</td><td>c.68_69delAG</td><td>c.5946delT</td><td><italic>BRCA1</italic></td><td>No</td><td>No LOH</td><td></td><td></td><td></td></tr><tr><td>5</td><td>Invasive breast</td><td>DCIS<sup>b</sup></td><td>c.181 T > G</td><td>c.1318_1319dupCT</td><td>No</td><td><italic>BRCA2</italic></td><td>No LOH</td><td></td><td></td><td></td></tr><tr><td>6 L</td><td>Bilateral breast</td><td>DCIS<sup>b</sup></td><td>c.5251C > T</td><td>c.6753_6754delTT</td><td>No</td><td>No</td><td>No LOH<sup>d</sup></td><td></td><td></td><td></td></tr><tr><td>6R</td><td>Bilateral breast</td><td>DCIS<sup>b</sup></td><td>c.5251C > T</td><td>c.6753_6754delTT</td><td><italic>BRCA1</italic></td><td>No</td><td>No LOH<sup>d</sup></td><td></td><td></td><td></td></tr><tr><td>7</td><td>Invasive breast</td><td>DCIS<sup>b</sup></td><td>c.5266dupC</td><td>c.8364G > A</td><td>No</td><td><italic>BRCA1</italic></td><td>No LOH</td><td></td><td></td><td></td></tr><tr><td>8</td><td>Invasive breast</td><td>DCIS<sup>b</sup></td><td>c.3700_3704del5</td><td>c.681 + 1G > A</td><td><italic>BRCA1, BRCA2</italic></td><td><italic>BRCA1</italic></td><td><italic>BRCA1</italic> LOH</td><td></td><td></td><td></td></tr><tr><td>9</td><td>Invasive breast</td><td>DCIS<sup>b</sup></td><td>c.68_69delAG</td><td>c.5946delT</td><td><italic>BRCA2</italic></td><td><italic>BRCA1, BRCA2</italic></td><td><italic>BRCA2</italic> LOH</td><td></td><td></td><td></td></tr><tr><td>10</td><td>Invasive breast</td><td>Inv Br</td><td>c.68_69delAG</td><td>c.5946delT</td><td><italic>BRCA1, BRCA2</italic></td><td>Failed</td><td>Failed<sup>c</sup></td><td></td><td></td><td></td></tr><tr><td>11<sup>a</sup></td><td>Invasive breast</td><td>Inv Br</td><td>c.3770_3771delAG</td><td>c.5946delT</td><td><sup>a</sup></td><td><sup>a</sup></td><td><italic>BRCA2</italic> LOH</td><td></td><td></td><td></td></tr><tr><td>12<sup>a</sup></td><td>Breast</td><td>Inv Br</td><td>c.68_69delAG</td><td>c.5946delT</td><td><sup>a</sup></td><td><sup>a</sup></td><td>No LOH</td><td></td><td></td><td></td></tr><tr><td>2</td><td>Ovary</td><td>Ov</td><td>c.1793 T > A</td><td>c.8537_8538delAG</td><td></td><td></td><td></td><td><italic>BRCA1</italic></td><td><italic>BRCA1</italic></td><td><italic>BRCA1</italic> LOH</td></tr><tr><td>4</td><td>Ovary</td><td>Ov</td><td>c.68_69delAG</td><td>c.5946delT</td><td></td><td></td><td></td><td>No</td><td>No</td><td>No LOH</td></tr><tr><td>12<sup>a</sup></td><td>Ovary</td><td>Ov</td><td>c.68_69delAG</td><td>c.5946delT</td><td><sup>a</sup></td><td><sup>a</sup></td><td>No</td><td><sup>a</sup></td><td><sup>a</sup></td><td>No LOH</td></tr></tbody></table><table-wrap-foot><p>See also Additional file <xref rid="MOESM1" ref-type="media">1</xref> (Table S5)</p><p><sup>a</sup>Previously published, <sup>b</sup>with micro-invasion, <sup>c</sup>case failed due to no PCR amplification in the sequencing, <sup>d</sup>no LOH in either the right or left breast tumor</p><p><italic>DCIS</italic> ductal carcinoma <italic>in situ</italic>, <italic>Inv Br</italic> invasive breast cancer, <italic>LOH</italic> loss of heterozygosity, <italic>Ov</italic> ovarian cancer</p></table-wrap-foot></table-wrap></p></sec></sec><sec id="Sec9"><title>Discussion</title><p>This study describes the characteristics of TH compared with SH1 and SH2 mutation carriers and supplements the existing literature regarding LOH in TH. Previously, 35 female TH individuals have been reported in the literature in a series of papers [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR14">14</xref>, <xref ref-type="bibr" rid="CR20">20</xref>, <xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR35">35</xref>, <xref ref-type="bibr" rid="CR36">36</xref>]. Only three relatively small studies have so far compared the characteristics of TH to SH women. Lavie et al. [<xref ref-type="bibr" rid="CR20">20</xref>] reported a non-significant difference in BC occurrence; seven of the 16 TH women (46.7 %) had a personal history of breast carcinoma compared with 372 of 926 (40.2 %) carriers of a single mutation (odds ratio (OR) = 1.3, 95 % confidence interval (CI) 0.4–4.0) [<xref ref-type="bibr" rid="CR20">20</xref>]. The mean age at diagnosis in TH was 44.6 years, compared with 48.1 in SH. In contrast, Heidemann et al. [<xref ref-type="bibr" rid="CR14">14</xref>] based on a study of 8 TH individuals suggested that TH develop BC at an earlier age and have more severe disease than those with single heterozygous <italic>BRCA</italic> mutation [<xref ref-type="bibr" rid="CR14">14</xref>]. Zuradelli et al. [<xref ref-type="bibr" rid="CR39">39</xref>] reported TH, and provided the possible association between TH and gastric cancer. Similar to the results from the study by Lavie et al. on 16 Ashkenazi Jewish female TH [<xref ref-type="bibr" rid="CR20">20</xref>], we report that TH were more likely than both SH1 or SH2 to be diagnosed with BC, which was also observed in our series. In addition to prior reports, we observed that TH were more likely to be diagnosed with OC compared with SH2s, but not compared with with SH1s. TH breast tumors were more likely to be ER-/PR-positive than in SH1, but less likely than in SH2 patients, without other different tumor or disease characteristics.</p><p>A number of TH had not been diagnosed with cancer by the time this analysis was completed. Twenty-five TH in our cohort had no BC or OC diagnosis at the time of counseling or genotyping. The average age of these TH individuals was 39.1 years (range 20–68). Of these, 16 (64 %) were less than 41 years old at the time of study, which is the average age of BC diagnosis, and 23 (92 %) were younger than the average age of OC diagnosis (54 years) in the CIMBA data. Of these 25 unaffected TH women, 7 (28 %) reported a RRSO compared to 2751 (22.6 %) who underwent RRSO among the total set of SH controls without BC or OC (12,154). Two (8.0 %) cancer-free TH underwent bilateral risk-reducing mastectomy compared to 1076 (8.9 %) SH. In addition, we had missing data for a number of relevant variables that could have impacted some inferences. For example, of the 62 breast cancers in the TH groups, only 21 (34 %) reported stage information.</p><p>Although this is the largest series of TH women reported to date, the study is still limited in a number of ways. TH were more likely to be born more recently (i.e., since 1961) than SH2, but not SH1. Since there is evidence that birth cohort may have an important effect on cancer risk [<xref ref-type="bibr" rid="CR18">18</xref>], the risk associations reported here may require additional evaluation in the future. The higher incidence of BC in the TH group versus both SH1 and SH2 groups, and of OC in the TH vs. the SH2 cohort could be explained by non-random inclusion of TH in the sample, leading to potential biases in associations, and this may limit generalizability of the dataset. Our analyses also do not account for potentially important confounders and the longitudinal nature of the data to follow cancer cases from time of testing to either cancer diagnosis or censoring after risk-reducing surgery. Furthermore, the great majority of missing data on cancer features avoids that certain questions may be appropriately addressed from this type of dataset. Additional future studies are required to completely evaluate these clinically important unresolved issues, and hopefully with the ongoing multinational collaboration within consortia like CIMBA this will be possible in time.</p><p>Differences in breast tumor hormone receptor status suggest that TH cases developing BC have an intermediate cancer phenotype between <italic>BRCA1</italic> and <italic>BRCA2</italic>, which would be consistent with the tumors being driven by loss of either <italic>BRCA1</italic> or <italic>BRCA2</italic>. We attempted to determine the frequency of loss of each gene in a subset of cases where tumor material was available. Previously published data suggest a high rate of LOH with loss of the normal allele in the majority of BRCA1 and BRCA2 cases with strong family history at approximately 80 and 70 years, respectively [<xref ref-type="bibr" rid="CR24">24</xref>]. However, we did not find loss of either <italic>BRCA1</italic> or <italic>BRCA2</italic> in the majority of tumors. The low frequency of LOH was consistent with the results from a previously published case (case 12) where we did not find LOH of either gene in either the breast or ovarian tumor [<xref ref-type="bibr" rid="CR27">27</xref>]. Three other papers on TH showed LOH with loss of the normal allele [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR35">35</xref>]. One potential reason for the low frequency of LOH in this study could be that seven of the breast tumor samples were areas of ductal carcinoma <italic>in</italic> situ (DCIS) with micro-invasion rather than a region of the invasive breast tumor. However, we identified two tumors with LOH in these types of samples so this explanation is unlikely to be the major cause of the low rate of LOH.</p><p>The observed ages at diagnosis of BC in TH, SH1, and SH2, and the distributions of tumor characteristics may also reveal the interactions of <italic>BRCA1</italic> and <italic>BRCA2</italic> mutations, which may have implications for modeling the cancer susceptibility in TH. The observed age distributions rule out a multiplicative model for the interactions of <italic>BRCA1</italic> and <italic>BRCA2</italic> mutations on BC risk. Given the well-established BC risks for <italic>BRCA1</italic> and <italic>BRCA2</italic> mutations, a multiplicative model would imply very high cancer risk at young ages. However, the present study suggests that ages at BC diagnosis in TH are not significantly different from those in <italic>BRCA1</italic> mutation carriers. Therefore, a multiplicative model of cancer risk for <italic>BRCA1</italic> and <italic>BRCA2</italic> is inconsistent with the current observations. This observation, combined with the fact that the tumor characteristics are intermediate to SH1 and SH2, suggests that an additive model for the joint effects of <italic>BRCA1</italic> and <italic>BRCA2</italic> mutations is more plausible. These results could be used for modeling the cancer risks for TH carriers and could be incorporated into risk prediction models.</p><p>Micro-satellite analysis alone did show a decrease in one of the two alleles in more of the tumors (6 out of 12 <italic>BRCA1</italic> and 5 out of 12 <italic>BRCA2</italic>); however, the sequencing data suggested that the mutant allele rather than the normal allele was lost in many of the tumors. Although the early publications in high-risk families showed very high rates of LOH, exclusively with loss of the normal allele, more recently there have been many publications showing larger numbers of cases with no LOH [<xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR24">24</xref>] and an increasing number of tumors with loss of the mutant allele [<xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]. The second hit in these tumors could be due to a somatic mutation of the normal chromosome or due to promoter methylation, rather than LOH. Unfortunately, the amount of material from these tumors was very limited, and it was not possible to preform additional experiments to investigate alternative mechanisms. Methylation of <italic>BRCA1</italic> has been shown to be a mechanism of decreased <italic>BRCA1</italic> expression in sporadic BC [<xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR34">34</xref>], although this is less frequent in <italic>BRCA1</italic> carriers [<xref ref-type="bibr" rid="CR10">10</xref>, <xref ref-type="bibr" rid="CR33">33</xref>]. Why the mechanism of LOH with loss of the normal allele in TH might be different compared with SH is unclear. Tumor material was only available in a small proportion of the cases with cancer. Therefore, it is difficult to interpret the results of the tumor study more broadly. Despite the small numbers, we did not find evidence to support the hypothesis that the tumors would either have LOH of <italic>BRCA1</italic> or <italic>BRCA2</italic>. The TH breast tumor characteristics, however, do appear to be intermediate in phenotype to SH1 and SH2, suggesting some cancers are being driven by inactivation of <italic>BRCA1</italic> and some by inactivation of <italic>BRCA2</italic>. Additional studies that explore other causes of inactivation (e.g., methylation or somatic mutation) are warranted.</p></sec><sec id="Sec10"><title>Conclusions</title><p>We report evidence that the <italic>BRCA1</italic> mutation in TH may drive these clinical TH phenotypes based on elevated OC risk in TH vs. SH2 but not SH1, and earlier age of BC diagnosis in TH vs. SH2 but not SH1. Therefore, TH may be managed more like BRCA1 mutation carriers than BRCA2 mutation carriers. In contrast, TH breast tumor characteristics (e.g., ER/PR status) are intermediate in phenotype to SH1 and SH2. Future studies are warranted to understand whether TH should be managed differently to SH1 or SH2 carriers, and, if so, to enable individualized counseling and clinical management appropriate for TH mutation carriers.</p></sec></body><back><app-group><app id="App1"><sec id="Sec11"><title>Additional files</title><p><media position="anchor" xlink:href="13058_2016_768_MOESM1_ESM.doc" id="MOESM1"><label>Additional file 1: Table S1.</label><caption><p>Ethics committees that granted approval for the access and use of the data for this study. <bold>Table S2.</bold> Participant counts by center and mutation. <bold>Table S3.</bold> Primers used for PCR and Sanger sequencing. <bold>Table S4.</bold> Primers used in micro-satellite analysis for loss of heterozygosity. <bold>Table S5.</bold> Micro-satellite loss of heterozygosity and sequencing analysis results. (DOC 177 kb)</p></caption></media></p></sec></app></app-group><glossary><title>Abbreviations</title><def-list><def-item><term>BC</term><def><p>Breast cancer</p></def></def-item><def-item><term>CIMBA</term><def><p>Consortium of Investigators of Modifiers of <italic>BRCA1/2</italic></p></def></def-item><def-item><term>DCIS</term><def><p>Ductal carcinoma <italic>in situ</italic></p></def></def-item><def-item><term>ER</term><def><p>Estrogen receptor</p></def></def-item><def-item><term>LOH</term><def><p>Loss of heterozygosity</p></def></def-item><def-item><term>OC</term><def><p>Ovarian cancer</p></def></def-item><def-item><term>PTC</term><def><p>Premature termination codon</p></def></def-item><def-item><term>PR</term><def><p>Progesterone receptor</p></def></def-item><def-item><term>RRSO</term><def><p>Risk-reducing salpingo-oophorectomy</p></def></def-item><def-item><term>SH1</term><def><p>Single mutation at <italic>BRCA1</italic></p></def></def-item><def-item><term>SH2</term><def><p>Single mutation at <italic>BRCA2</italic></p></def></def-item><def-item><term>TH</term><def><p>Transheterozygosity, transheterozygote</p></def></def-item></def-list></glossary><ack><p>ACA and the CIMBA data management are funded by Cancer Research UK (C12292/A20861 and C12292/A11174). TRR was supported by R01-CA083855, R01-CA102776, and P50-CA083638. KLN, TMF, and SMD are supported by the Basser Research Center at the University of Pennsylvania. BP is supported by R01-CA112520. Cancer Research UK provided financial support for this work. ACA is a Senior Cancer Research UK Cancer Research Fellow. DFE is Cancer Research UK Principal Research Fellow. Tumor analysis was funded by STOP CANCER (to SJR). Study-specific acknowledgements are as follows:</p><p><table-wrap id="Taba"><table frame="hsides" rules="groups"><tbody><tr><td><bold>Study</bold></td><td><bold>Funding</bold></td><td><bold>Acknowledgements</bold></td></tr><tr><td>BCFR - all</td><td>This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.</td><td></td></tr><tr><td>BCFR-AU</td><td></td><td>Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis.</td></tr><tr><td>BCFR-NY</td><td></td><td>We wish to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study.</td></tr><tr><td>BCFR-ON</td><td></td><td>We wish to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study.</td></tr><tr><td>BFBOCC-LT</td><td>BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015</td><td>BFBOCC-LT acknowledge Vilius Rudaitis and Laimonas Griškevičius. BFBOCC-LV acknowledge Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics.</td></tr><tr><td>BIDMC</td><td>BIDMC is supported by the Breast Cancer Research Foundation</td><td></td></tr><tr><td>BMBSA</td><td>BRCA gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg</td><td>BMBSA wish to thank the families who contribute to the BMBSA study</td></tr><tr><td>BRICOH</td><td>SLN was partially supported by the Morris and Horowitz Families Endowed Professorship.</td><td>We wish to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management.</td></tr><tr><td>CBCS</td><td></td><td>We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants</td></tr><tr><td>CNIO</td><td>This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493</td><td>We thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance.</td></tr><tr><td>COH-CCGCRN</td><td>City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health</td><td></td></tr><tr><td>CONSIT TEAM</td><td>Funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’) to SM.</td><td>Bernard Peissel, Jacopo Azzollini and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Bernardo Bonanni, Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia, Milan, Italy; Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano (PN), Italy; Barbara Pasini and Francesca Vignolo-Lutati of the University of Turin, Turin, Italy; Laura Papi and Gabriele Capone of the University of Florence, Florence, Italy; Laura Ottini and Giuseppe Giannini of the “Sapienza” University, Rome, Italy; Liliana Varesco of the IRCCS AOU San Martino – IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Maria Grazia Tibiletti of the Ospedale di Circolo-Università dell’Insubria, Varese, Italy; Antonella Savarese and Aline Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy; Stefania Tommasi of the Istituto Nazionale Tumori “Giovanni Paolo II” - Bari, Italy.</td></tr><tr><td>CORE</td><td>The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow.</td><td>UK grants C12292/A20861. We wish to thank Sue Healey for her many contributions to CIMBA.</td></tr><tr><td>DEMOKRITOS</td><td>This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund.</td><td></td></tr><tr><td>DKFZ</td><td>The DKFZ study was supported by the DKFZ.</td><td></td></tr><tr><td>EMBRACE</td><td>EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust</td><td>RE is supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust</td></tr><tr><td>FCCC</td><td>The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship.</td><td>We thank Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support.</td></tr><tr><td>GC-HBOC</td><td>The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837), Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC)</td><td></td></tr><tr><td>GEMO</td><td>The study was supported by the Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award; the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa).</td><td>Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study : National Cancer Genetics Network «UNICANCER Genetic Group», France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014, and to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, & Equipe «Génétique du cancer du sein», Centre de Recherche en Cancérologie de Lyon: Olga Sinilnikova†, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Mélanie Léone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnès Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona, Sandrine Handallou. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin†, Claude Adenis. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU Limoges: Laurence Vénat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy : Johanna Sokolowska, Myriam Bronner. CHU Besançon: Marie-Agnès Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder.</td></tr><tr><td>GEORGETOWN</td><td>CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure.</td><td></td></tr><tr><td>HCSC</td><td>Was supported by a grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER funds</td><td>We acknowledge Alicia Tosar and Paula Diaque for their technical assistance</td></tr><tr><td>HEBCS</td><td>The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation.</td><td>HEBCS would like to thank Dr. Kristiina Aittomäki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkilä and Virpi Palola for their help with the HEBCS data and samples.</td></tr><tr><td>HEBON</td><td>The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection.</td><td>The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection.</td></tr><tr><td>HRBCP</td><td>HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong</td><td>We wish to thank Hong Kong Sanatorium and Hospital for their continued support</td></tr><tr><td>HUNBOCS</td><td>Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9</td><td>We wish to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study.</td></tr><tr><td>HVH</td><td></td><td>We wish to thank the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron. Acknowledgements to the Cellex Foundation for providing research facilities and equipment.</td></tr><tr><td>ICO</td><td>ICO: Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364.</td><td>We wish to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella.</td></tr><tr><td>IHCC</td><td>The IHCC was supported by Grant PBZ_KBN_122/P05/2004</td><td></td></tr><tr><td>INHERIT</td><td>This work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701.</td><td>We would like to thank Dr Martine Dumont, Martine Tranchant for sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (BCAC and CIMBA).</td></tr><tr><td>IOCHBOCS</td><td>IOCHBOCS is supported by Ministero della Salute and “5×1000” Istituto Oncologico Veneto grant.</td><td></td></tr><tr><td>IPOBCS</td><td>This study was in part supported by Liga Portuguesa Contra o Cancro.</td><td>We wish to thank Drs. Ana Peixoto, Catarina Santos, Patrícia Rocha and Pedro Pinto for their skillful contribution to the study.</td></tr><tr><td>KCONFAB</td><td>kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia;</td><td>We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab.</td></tr><tr><td>KOHBRA</td><td>KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350).</td><td></td></tr><tr><td>MAYO</td><td>MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation.</td><td></td></tr><tr><td>MCGILL</td><td>Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade</td><td></td></tr><tr><td>MODSQUAD</td><td>MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ).</td><td>Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic).</td></tr><tr><td>MSKCC</td><td>MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund.</td><td>Anne Lincoln, Lauren Jacobs</td></tr><tr><td>NCI</td><td>The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. For CIMBA PRS paper: The research of Drs. MH Greene and JT Loud was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD.</td><td></td></tr><tr><td>NNPIO</td><td>This work has been supported by the Russian Federation for Basic Research (grants 14-04-93959 and 15-04-01744).</td><td></td></tr><tr><td>NRG Oncology</td><td>This study was supported by NRG Oncology Operations grant number U10 CA180868 as well as NRG SDMC grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469) and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI.</td><td>We thank the investigators of the Australia New Zealand NRG Oncology group</td></tr><tr><td>OCGN</td><td></td><td>We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study.</td></tr><tr><td>OSU CCG</td><td>OSUCCG is supported by the Ohio State University Comprehensive Cancer Center.</td><td>Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records and database management.</td></tr><tr><td>PBCS</td><td>This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013.</td><td></td></tr><tr><td>SEABASS</td><td>Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation</td><td>We would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively. The Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from Cancer Research Initiatives Foundation.</td></tr><tr><td>SMC</td><td>This project was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited breast cancer consortium</td><td>SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study.</td></tr><tr><td>SWE-BRCA</td><td>SWE-BRCA collaborators are supported by the Swedish Cancer Society</td><td>Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren</td></tr><tr><td>UCHICAGO</td><td>UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor.</td><td>We wish to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program.</td></tr><tr><td>UCLA</td><td>Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation</td><td>We thank Joyce Seldon MSGC and Lorna Kwan, MPH for assembling the data for this study.</td></tr><tr><td>UCSF</td><td>UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center</td><td>We would like to thank Dr. Robert Nussbaum and the following genetic counselors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad. And thanks to Ms. Salina Chan for her data management.</td></tr><tr><td>UKFOCR</td><td>UKFOCR was supported by a project grant from CRUK to Paul Pharoah.</td><td>We thank Simon Gayther, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR.</td></tr><tr><td>UPENN</td><td>National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA</td><td></td></tr><tr><td>UPITT/MWH</td><td>Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program;Hackers for Hope Pittsburgh</td><td></td></tr><tr><td>VFCTG</td><td>Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation</td><td>Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification.</td></tr><tr><td>WCP</td><td>Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124</td><td></td></tr><tr><td></td><td>Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund .</td><td></td></tr></tbody></table></table-wrap></p><sec id="FPar1"><title>Funding</title><p>Described above.</p></sec><sec id="FPar2"><title>Authors’ contributions</title><p>The following authors made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, and were involved in drafting the manuscript or revising it critically for important intellectual content: TRR, TMF, NM, FW, SC, ILA, PA, NA, BKA, DB, JB, RB, PB, AB, SSB, TC, JCa, JCh, KBMC, FJC, CC, MBD, MdlH, OD, SMD, KLN, KD, SE, EMBRACE, DGE, LF, EF, DF, PAG, JGa, GG, AKG, MHG, JGr, EHah, EHal, UH, TVOH, HEBON, ENI, CI, AJ, RJ, KJ-B, EMJ, BYK, BK, KConFab Investigators, AK, YL, CLas, CLaz, JLe, NL, JLu, SM, GM, MM, SLN, HN, DN, RLN, KO, EO, OIO, SKP, MP, PR, CR-F, MAR, CS, JS, CFS, PS, MS, DS-L, GS, CIS, MTa, MRT, S-HT, MBT, MTh, LT, MTi, AET, AT-G, NT, EJvR, DV, SW-G, BW, JNW, JZ, KKZ, LM, DE, GC-T, ACA, and SJR. The following authors were involved in the statistical analysis and oversaw the writing of the manuscript: TRR, TMF, NM, FW, ACA, and SJR. The following author was responsible for the laboratory data generation and analysis: SJR. All authors have given final approval of the version to be published and have participated sufficiently in the work to take public responsibility for appropriate portions of the content. All authors have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.</p></sec><sec id="FPar3"><title>Competing interests</title><p>The authors declare that they have no competing interests.</p></sec><sec id="FPar4"><title>Ethics approval and consent to participate</title><p>Ethics approval was obtained at each participating center for the collection of the data described in this report. 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