Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.
Identifieur interne : 001C80 ( PubMed/Corpus ); précédent : 001C79; suivant : 001C81Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.
Auteurs : Miguel De La Hoya ; Omar Soukarieh ; Irene L Pez-Perolio ; Ana Vega ; Logan C. Walker ; Yvette Van Ierland ; Diana Baralle ; Marta Santamari A ; Vanessa Lattimore ; Juul Wijnen ; Philip Whiley ; Ana Blanco ; Michela Raponi ; Jan Hauke ; Barbara Wappenschmidt ; Alexandra Becker ; Thomas V O. Hansen ; Raquel Behar ; Kconfab Investigators ; Diether Niederacher ; Norbert Arnold ; Bernd Dworniczak ; Doris Steinemann ; Ulrike Faust ; Wendy Rubinstein ; Peter J. Hulick ; Claude Houdayer ; Sandrine M. Caputo ; Laurent Castera ; Tina Pesaran ; Elizabeth Chao ; Carole Brewer ; Melissa C. Southey ; Christi J. Van Asperen ; Christian F. Singer ; Jan Sullivan ; Nicola Poplawski ; Phuong Mai ; Julian Peto ; Nichola Johnson ; Barbara Burwinkel ; Harald Surowy ; Stig E. Bojesen ; Henrik Flyger ; Annika Lindblom ; Sara Margolin ; Jenny Chang-Claude ; Anja Rudolph ; Paolo Radice ; Laura Galastri ; Janet E. Olson ; Emily Hallberg ; Graham G. Giles ; Roger L. Milne ; Irene L. Andrulis ; Gord Glendon ; Per Hall ; Kamila Czene ; Fiona Blows ; Mitul Shah ; Qin Wang ; Joe Dennis ; Kyriaki Michailidou ; Lesley Mcguffog ; Manjeet K. Bolla ; Antonis C. Antoniou ; Douglas F. Easton ; Fergus J. Couch ; Sean Tavtigian ; Maaike P. Vreeswijk ; Michael Parsons ; Huong D. Meeks ; Alexandra Martins ; David E. Goldgar ; Amanda B. SpurdleSource :
- Human molecular genetics [ 1460-2083 ] ; 2016.
English descriptors
- KwdEn :
- Adult, Aged, Alternative Splicing (genetics), BRCA1 Protein (genetics), Breast Neoplasms (genetics), Breast Neoplasms (pathology), DNA Mutational Analysis, Exons (genetics), Female, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Mutation (genetics), Ovarian Neoplasms (genetics), Ovarian Neoplasms (pathology), RNA Splice Sites (genetics), RNA Splicing (genetics), Tumor Suppressor Proteins (genetics).
- MESH :
- chemical , genetics : BRCA1 Protein, RNA Splice Sites, Tumor Suppressor Proteins.
- genetics : Alternative Splicing, Breast Neoplasms, Exons, Mutation, Ovarian Neoplasms, RNA Splicing.
- pathology : Breast Neoplasms, Ovarian Neoplasms.
- Adult, Aged, DNA Mutational Analysis, Female, Gene Expression Regulation, Neoplastic, Humans, Middle Aged.
Abstract
A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10(-8) Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
DOI: 10.1093/hmg/ddw094
PubMed: 27008870
Links to Exploration step
pubmed:27008870Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.</title><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:affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain amanda.spurdle@qimr.edu.au mhoya@hotmail.com.</nlm:affiliation></affiliation></author><author><name sortKey="Soukarieh, Omar" sort="Soukarieh, Omar" uniqKey="Soukarieh O" first="Omar" last="Soukarieh">Omar Soukarieh</name><affiliation><nlm:affiliation>Inserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="L Pez Perolio, Irene" sort="L Pez Perolio, Irene" uniqKey="L Pez Perolio I" first="Irene" last="L Pez-Perolio">Irene L Pez-Perolio</name><affiliation><nlm:affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Vega, Ana" sort="Vega, Ana" uniqKey="Vega A" first="Ana" last="Vega">Ana Vega</name><affiliation><nlm:affiliation>Fundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Walker, Logan C" sort="Walker, Logan C" uniqKey="Walker L" first="Logan C" last="Walker">Logan C. Walker</name><affiliation><nlm:affiliation>Department of Pathology, University of Otago, Christchurch 8140, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Van Ierland, Yvette" sort="Van Ierland, Yvette" uniqKey="Van Ierland Y" first="Yvette" last="Van Ierland">Yvette Van Ierland</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Baralle, Diana" sort="Baralle, Diana" uniqKey="Baralle D" first="Diana" last="Baralle">Diana Baralle</name><affiliation><nlm:affiliation>Human Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Santamari A, Marta" sort="Santamari A, Marta" uniqKey="Santamari A M" first="Marta" last="Santamari A">Marta Santamari A</name><affiliation><nlm:affiliation>CIBERER, Grupo de Medicina Xenómica-USC, Universidade de Santiago de Compostela, Fundacion Galega de Medicina Xenómica (SERGAS), Santiago de Compostela 15706, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Lattimore, Vanessa" sort="Lattimore, Vanessa" uniqKey="Lattimore V" first="Vanessa" last="Lattimore">Vanessa Lattimore</name><affiliation><nlm:affiliation>Department of Pathology, University of Otago, Christchurch 8140, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Wijnen, Juul" sort="Wijnen, Juul" uniqKey="Wijnen J" first="Juul" last="Wijnen">Juul Wijnen</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Whiley, Philip" sort="Whiley, Philip" uniqKey="Whiley P" first="Philip" last="Whiley">Philip Whiley</name><affiliation><nlm:affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blanco, Ana" sort="Blanco, Ana" uniqKey="Blanco A" first="Ana" last="Blanco">Ana Blanco</name><affiliation><nlm:affiliation>Fundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Raponi, Michela" sort="Raponi, Michela" uniqKey="Raponi M" first="Michela" last="Raponi">Michela Raponi</name><affiliation><nlm:affiliation>Human Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hauke, Jan" sort="Hauke, Jan" uniqKey="Hauke J" first="Jan" last="Hauke">Jan Hauke</name><affiliation><nlm:affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation><nlm:affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Alexandra" sort="Becker, Alexandra" uniqKey="Becker A" first="Alexandra" last="Becker">Alexandra Becker</name><affiliation><nlm:affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</nlm:affiliation></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:affiliation>Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen DK-2100, Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="Behar, Raquel" sort="Behar, Raquel" uniqKey="Behar R" first="Raquel" last="Behar">Raquel Behar</name><affiliation><nlm:affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Investigators, Kconfab" sort="Investigators, Kconfab" uniqKey="Investigators K" first="Kconfab" last="Investigators">Kconfab Investigators</name><affiliation><nlm:affiliation>Peter MacCallum Cancer Center, University of Melbourne, Melbourne, VIC 3002, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Niederacher, Diether" sort="Niederacher, Diether" uniqKey="Niederacher D" first="Diether" last="Niederacher">Diether Niederacher</name><affiliation><nlm:affiliation>Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Arnold, Norbert" sort="Arnold, Norbert" uniqKey="Arnold N" first="Norbert" last="Arnold">Norbert Arnold</name><affiliation><nlm:affiliation>Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel 24105, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Dworniczak, Bernd" sort="Dworniczak, Bernd" uniqKey="Dworniczak B" first="Bernd" last="Dworniczak">Bernd Dworniczak</name><affiliation><nlm:affiliation>Institute of Human Genetics, University of Münster, Münster 48149, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Steinemann, Doris" sort="Steinemann, Doris" uniqKey="Steinemann D" first="Doris" last="Steinemann">Doris Steinemann</name><affiliation><nlm:affiliation>Institute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Faust, Ulrike" sort="Faust, Ulrike" uniqKey="Faust U" first="Ulrike" last="Faust">Ulrike Faust</name><affiliation><nlm:affiliation>Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen 72076, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rubinstein, Wendy" sort="Rubinstein, Wendy" uniqKey="Rubinstein W" first="Wendy" last="Rubinstein">Wendy Rubinstein</name><affiliation><nlm:affiliation>National Institutes of Health, Bethesda, MD 20892-2152, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hulick, Peter J" sort="Hulick, Peter J" uniqKey="Hulick P" first="Peter J" last="Hulick">Peter J. Hulick</name><affiliation><nlm:affiliation>Center for Medical Genetics, NorthShore University Health System, University of Chicago Pritzker School of Medicine, Evanston, IL 60201, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Houdayer, Claude" sort="Houdayer, Claude" uniqKey="Houdayer C" first="Claude" last="Houdayer">Claude Houdayer</name><affiliation><nlm:affiliation>Service de Génétique, Department de Biologie des Tumeurs, Institut Curie and INSERM U830, Centre de Recherche de l'Institut Curie, Paris, and Universite Paris Descartes, Sorbonne Paris Cite, Paris 75248, France.</nlm:affiliation></affiliation></author><author><name sortKey="Caputo, Sandrine M" sort="Caputo, Sandrine M" uniqKey="Caputo S" first="Sandrine M" last="Caputo">Sandrine M. Caputo</name><affiliation><nlm:affiliation>Service de Génétique, Department de Biologie des Tumeurs, Institut Curie, Paris 75248, France.</nlm:affiliation></affiliation></author><author><name sortKey="Castera, Laurent" sort="Castera, Laurent" uniqKey="Castera L" first="Laurent" last="Castera">Laurent Castera</name><affiliation><nlm:affiliation>Centre Francois Baclesse, Laboratoire de Biologie et de Genetique du Cancer, 14076 Caen, Paris 75248, France.</nlm:affiliation></affiliation></author><author><name sortKey="Pesaran, Tina" sort="Pesaran, Tina" uniqKey="Pesaran T" first="Tina" last="Pesaran">Tina Pesaran</name><affiliation><nlm:affiliation>Ambry Genetics, Aliso Viejo, CA 92656, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chao, Elizabeth" sort="Chao, Elizabeth" uniqKey="Chao E" first="Elizabeth" last="Chao">Elizabeth Chao</name><affiliation><nlm:affiliation>Ambry Genetics, Aliso Viejo, CA 92656, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Brewer, Carole" sort="Brewer, Carole" uniqKey="Brewer C" first="Carole" last="Brewer">Carole Brewer</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name><affiliation><nlm:affiliation>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Van Asperen, Christi J" sort="Van Asperen, Christi J" uniqKey="Van Asperen C" first="Christi J" last="Van Asperen">Christi J. Van Asperen</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></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:affiliation>Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.</nlm:affiliation></affiliation></author><author><name sortKey="Sullivan, Jan" sort="Sullivan, Jan" uniqKey="Sullivan J" first="Jan" last="Sullivan">Jan Sullivan</name><affiliation><nlm:affiliation>Genetic Health Service NZ, South Island Hub, Christchurch Hospital, Christchurch 8140, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Poplawski, Nicola" sort="Poplawski, Nicola" uniqKey="Poplawski N" first="Nicola" last="Poplawski">Nicola Poplawski</name><affiliation><nlm:affiliation>Adult Genetics Unit, South Australian Clinical Genetics Service, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5067, Australia University Department of Paediatrics, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Mai, Phuong" sort="Mai, Phuong" uniqKey="Mai P" first="Phuong" last="Mai">Phuong Mai</name><affiliation><nlm:affiliation>Clinical Genetics Branch, DCEG, NCI, NIH, Bethesda, MD, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Peto, Julian" sort="Peto, Julian" uniqKey="Peto J" first="Julian" last="Peto">Julian Peto</name><affiliation><nlm:affiliation>London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Johnson, Nichola" sort="Johnson, Nichola" uniqKey="Johnson N" first="Nichola" last="Johnson">Nichola Johnson</name><affiliation><nlm:affiliation>Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Burwinkel, Barbara" sort="Burwinkel, Barbara" uniqKey="Burwinkel B" first="Barbara" last="Burwinkel">Barbara Burwinkel</name><affiliation><nlm:affiliation>Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Surowy, Harald" sort="Surowy, Harald" uniqKey="Surowy H" first="Harald" last="Surowy">Harald Surowy</name><affiliation><nlm:affiliation>Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E" last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:affiliation>Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen 2730, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1165, Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="Flyger, Henrik" sort="Flyger, Henrik" uniqKey="Flyger H" first="Henrik" last="Flyger">Henrik Flyger</name><affiliation><nlm:affiliation>Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="Lindblom, Annika" sort="Lindblom, Annika" uniqKey="Lindblom A" first="Annika" last="Lindblom">Annika Lindblom</name><affiliation><nlm:affiliation>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Margolin, Sara" sort="Margolin, Sara" uniqKey="Margolin S" first="Sara" last="Margolin">Sara Margolin</name><affiliation><nlm:affiliation>Department of Oncology Pathology, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:affiliation>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:affiliation>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name><affiliation><nlm:affiliation>Unit of "Molecular bases of genetic risk and genetic testing", Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20139, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Galastri, Laura" sort="Galastri, Laura" uniqKey="Galastri L" first="Laura" last="Galastri">Laura Galastri</name><affiliation><nlm:affiliation>Associazione Volontari Italiani Sangue (AVIS) comunale di Milano, Milano 20139, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E" last="Olson">Janet E. Olson</name><affiliation><nlm:affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hallberg, Emily" sort="Hallberg, Emily" uniqKey="Hallberg E" first="Emily" last="Hallberg">Emily Hallberg</name><affiliation><nlm:affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G" last="Giles">Graham G. Giles</name><affiliation><nlm:affiliation>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L" last="Milne">Roger L. Milne</name><affiliation><nlm:affiliation>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.</nlm:affiliation></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:affiliation>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, M5B 1W8, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Glendon, Gord" sort="Glendon, Gord" uniqKey="Glendon G" first="Gord" last="Glendon">Gord Glendon</name><affiliation><nlm:affiliation>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Blows, Fiona" sort="Blows, Fiona" uniqKey="Blows F" first="Fiona" last="Blows">Fiona Blows</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Shah, Mitul" sort="Shah, Mitul" uniqKey="Shah M" first="Mitul" last="Shah">Mitul Shah</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Qin" sort="Wang, Qin" uniqKey="Wang Q" first="Qin" last="Wang">Qin Wang</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Dennis, Joe" sort="Dennis, Joe" uniqKey="Dennis J" first="Joe" last="Dennis">Joe Dennis</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Michailidou, Kyriaki" sort="Michailidou, Kyriaki" uniqKey="Michailidou K" first="Kyriaki" last="Michailidou">Kyriaki Michailidou</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683, Nicosia, Cyprus.</nlm:affiliation></affiliation></author><author><name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bolla, Manjeet K" sort="Bolla, Manjeet K" uniqKey="Bolla M" first="Manjeet K" last="Bolla">Manjeet K. Bolla</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></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:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F" last="Easton">Douglas F. Easton</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></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:affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tavtigian, Sean" sort="Tavtigian, Sean" uniqKey="Tavtigian S" first="Sean" last="Tavtigian">Sean Tavtigian</name><affiliation><nlm:affiliation>Department of Oncological Sciences.</nlm:affiliation></affiliation></author><author><name sortKey="Vreeswijk, Maaike P" sort="Vreeswijk, Maaike P" uniqKey="Vreeswijk M" first="Maaike P" last="Vreeswijk">Maaike P. Vreeswijk</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Parsons, Michael" sort="Parsons, Michael" uniqKey="Parsons M" first="Michael" last="Parsons">Michael Parsons</name><affiliation><nlm:affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Meeks, Huong D" sort="Meeks, Huong D" uniqKey="Meeks H" first="Huong D" last="Meeks">Huong D. Meeks</name><affiliation><nlm:affiliation>Department of Oncological Sciences.</nlm:affiliation></affiliation></author><author><name sortKey="Martins, Alexandra" sort="Martins, Alexandra" uniqKey="Martins A" first="Alexandra" last="Martins">Alexandra Martins</name><affiliation><nlm:affiliation>Inserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E" last="Goldgar">David E. Goldgar</name><affiliation><nlm:affiliation>Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name><affiliation><nlm:affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia amanda.spurdle@qimr.edu.au mhoya@hotmail.com.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27008870</idno><idno type="pmid">27008870</idno><idno type="doi">10.1093/hmg/ddw094</idno><idno type="wicri:Area/PubMed/Corpus">001C80</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001C80</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.</title><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:affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain amanda.spurdle@qimr.edu.au mhoya@hotmail.com.</nlm:affiliation></affiliation></author><author><name sortKey="Soukarieh, Omar" sort="Soukarieh, Omar" uniqKey="Soukarieh O" first="Omar" last="Soukarieh">Omar Soukarieh</name><affiliation><nlm:affiliation>Inserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="L Pez Perolio, Irene" sort="L Pez Perolio, Irene" uniqKey="L Pez Perolio I" first="Irene" last="L Pez-Perolio">Irene L Pez-Perolio</name><affiliation><nlm:affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Vega, Ana" sort="Vega, Ana" uniqKey="Vega A" first="Ana" last="Vega">Ana Vega</name><affiliation><nlm:affiliation>Fundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Walker, Logan C" sort="Walker, Logan C" uniqKey="Walker L" first="Logan C" last="Walker">Logan C. Walker</name><affiliation><nlm:affiliation>Department of Pathology, University of Otago, Christchurch 8140, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Van Ierland, Yvette" sort="Van Ierland, Yvette" uniqKey="Van Ierland Y" first="Yvette" last="Van Ierland">Yvette Van Ierland</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Baralle, Diana" sort="Baralle, Diana" uniqKey="Baralle D" first="Diana" last="Baralle">Diana Baralle</name><affiliation><nlm:affiliation>Human Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Santamari A, Marta" sort="Santamari A, Marta" uniqKey="Santamari A M" first="Marta" last="Santamari A">Marta Santamari A</name><affiliation><nlm:affiliation>CIBERER, Grupo de Medicina Xenómica-USC, Universidade de Santiago de Compostela, Fundacion Galega de Medicina Xenómica (SERGAS), Santiago de Compostela 15706, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Lattimore, Vanessa" sort="Lattimore, Vanessa" uniqKey="Lattimore V" first="Vanessa" last="Lattimore">Vanessa Lattimore</name><affiliation><nlm:affiliation>Department of Pathology, University of Otago, Christchurch 8140, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Wijnen, Juul" sort="Wijnen, Juul" uniqKey="Wijnen J" first="Juul" last="Wijnen">Juul Wijnen</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Whiley, Philip" sort="Whiley, Philip" uniqKey="Whiley P" first="Philip" last="Whiley">Philip Whiley</name><affiliation><nlm:affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blanco, Ana" sort="Blanco, Ana" uniqKey="Blanco A" first="Ana" last="Blanco">Ana Blanco</name><affiliation><nlm:affiliation>Fundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Raponi, Michela" sort="Raponi, Michela" uniqKey="Raponi M" first="Michela" last="Raponi">Michela Raponi</name><affiliation><nlm:affiliation>Human Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hauke, Jan" sort="Hauke, Jan" uniqKey="Hauke J" first="Jan" last="Hauke">Jan Hauke</name><affiliation><nlm:affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation><nlm:affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Alexandra" sort="Becker, Alexandra" uniqKey="Becker A" first="Alexandra" last="Becker">Alexandra Becker</name><affiliation><nlm:affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</nlm:affiliation></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:affiliation>Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen DK-2100, Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="Behar, Raquel" sort="Behar, Raquel" uniqKey="Behar R" first="Raquel" last="Behar">Raquel Behar</name><affiliation><nlm:affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Investigators, Kconfab" sort="Investigators, Kconfab" uniqKey="Investigators K" first="Kconfab" last="Investigators">Kconfab Investigators</name><affiliation><nlm:affiliation>Peter MacCallum Cancer Center, University of Melbourne, Melbourne, VIC 3002, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Niederacher, Diether" sort="Niederacher, Diether" uniqKey="Niederacher D" first="Diether" last="Niederacher">Diether Niederacher</name><affiliation><nlm:affiliation>Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Arnold, Norbert" sort="Arnold, Norbert" uniqKey="Arnold N" first="Norbert" last="Arnold">Norbert Arnold</name><affiliation><nlm:affiliation>Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel 24105, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Dworniczak, Bernd" sort="Dworniczak, Bernd" uniqKey="Dworniczak B" first="Bernd" last="Dworniczak">Bernd Dworniczak</name><affiliation><nlm:affiliation>Institute of Human Genetics, University of Münster, Münster 48149, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Steinemann, Doris" sort="Steinemann, Doris" uniqKey="Steinemann D" first="Doris" last="Steinemann">Doris Steinemann</name><affiliation><nlm:affiliation>Institute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Faust, Ulrike" sort="Faust, Ulrike" uniqKey="Faust U" first="Ulrike" last="Faust">Ulrike Faust</name><affiliation><nlm:affiliation>Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen 72076, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rubinstein, Wendy" sort="Rubinstein, Wendy" uniqKey="Rubinstein W" first="Wendy" last="Rubinstein">Wendy Rubinstein</name><affiliation><nlm:affiliation>National Institutes of Health, Bethesda, MD 20892-2152, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hulick, Peter J" sort="Hulick, Peter J" uniqKey="Hulick P" first="Peter J" last="Hulick">Peter J. Hulick</name><affiliation><nlm:affiliation>Center for Medical Genetics, NorthShore University Health System, University of Chicago Pritzker School of Medicine, Evanston, IL 60201, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Houdayer, Claude" sort="Houdayer, Claude" uniqKey="Houdayer C" first="Claude" last="Houdayer">Claude Houdayer</name><affiliation><nlm:affiliation>Service de Génétique, Department de Biologie des Tumeurs, Institut Curie and INSERM U830, Centre de Recherche de l'Institut Curie, Paris, and Universite Paris Descartes, Sorbonne Paris Cite, Paris 75248, France.</nlm:affiliation></affiliation></author><author><name sortKey="Caputo, Sandrine M" sort="Caputo, Sandrine M" uniqKey="Caputo S" first="Sandrine M" last="Caputo">Sandrine M. Caputo</name><affiliation><nlm:affiliation>Service de Génétique, Department de Biologie des Tumeurs, Institut Curie, Paris 75248, France.</nlm:affiliation></affiliation></author><author><name sortKey="Castera, Laurent" sort="Castera, Laurent" uniqKey="Castera L" first="Laurent" last="Castera">Laurent Castera</name><affiliation><nlm:affiliation>Centre Francois Baclesse, Laboratoire de Biologie et de Genetique du Cancer, 14076 Caen, Paris 75248, France.</nlm:affiliation></affiliation></author><author><name sortKey="Pesaran, Tina" sort="Pesaran, Tina" uniqKey="Pesaran T" first="Tina" last="Pesaran">Tina Pesaran</name><affiliation><nlm:affiliation>Ambry Genetics, Aliso Viejo, CA 92656, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chao, Elizabeth" sort="Chao, Elizabeth" uniqKey="Chao E" first="Elizabeth" last="Chao">Elizabeth Chao</name><affiliation><nlm:affiliation>Ambry Genetics, Aliso Viejo, CA 92656, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Brewer, Carole" sort="Brewer, Carole" uniqKey="Brewer C" first="Carole" last="Brewer">Carole Brewer</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name><affiliation><nlm:affiliation>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Van Asperen, Christi J" sort="Van Asperen, Christi J" uniqKey="Van Asperen C" first="Christi J" last="Van Asperen">Christi J. Van Asperen</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></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:affiliation>Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.</nlm:affiliation></affiliation></author><author><name sortKey="Sullivan, Jan" sort="Sullivan, Jan" uniqKey="Sullivan J" first="Jan" last="Sullivan">Jan Sullivan</name><affiliation><nlm:affiliation>Genetic Health Service NZ, South Island Hub, Christchurch Hospital, Christchurch 8140, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Poplawski, Nicola" sort="Poplawski, Nicola" uniqKey="Poplawski N" first="Nicola" last="Poplawski">Nicola Poplawski</name><affiliation><nlm:affiliation>Adult Genetics Unit, South Australian Clinical Genetics Service, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5067, Australia University Department of Paediatrics, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Mai, Phuong" sort="Mai, Phuong" uniqKey="Mai P" first="Phuong" last="Mai">Phuong Mai</name><affiliation><nlm:affiliation>Clinical Genetics Branch, DCEG, NCI, NIH, Bethesda, MD, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Peto, Julian" sort="Peto, Julian" uniqKey="Peto J" first="Julian" last="Peto">Julian Peto</name><affiliation><nlm:affiliation>London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Johnson, Nichola" sort="Johnson, Nichola" uniqKey="Johnson N" first="Nichola" last="Johnson">Nichola Johnson</name><affiliation><nlm:affiliation>Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Burwinkel, Barbara" sort="Burwinkel, Barbara" uniqKey="Burwinkel B" first="Barbara" last="Burwinkel">Barbara Burwinkel</name><affiliation><nlm:affiliation>Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Surowy, Harald" sort="Surowy, Harald" uniqKey="Surowy H" first="Harald" last="Surowy">Harald Surowy</name><affiliation><nlm:affiliation>Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E" last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:affiliation>Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen 2730, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1165, Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="Flyger, Henrik" sort="Flyger, Henrik" uniqKey="Flyger H" first="Henrik" last="Flyger">Henrik Flyger</name><affiliation><nlm:affiliation>Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="Lindblom, Annika" sort="Lindblom, Annika" uniqKey="Lindblom A" first="Annika" last="Lindblom">Annika Lindblom</name><affiliation><nlm:affiliation>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Margolin, Sara" sort="Margolin, Sara" uniqKey="Margolin S" first="Sara" last="Margolin">Sara Margolin</name><affiliation><nlm:affiliation>Department of Oncology Pathology, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:affiliation>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:affiliation>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name><affiliation><nlm:affiliation>Unit of "Molecular bases of genetic risk and genetic testing", Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20139, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Galastri, Laura" sort="Galastri, Laura" uniqKey="Galastri L" first="Laura" last="Galastri">Laura Galastri</name><affiliation><nlm:affiliation>Associazione Volontari Italiani Sangue (AVIS) comunale di Milano, Milano 20139, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E" last="Olson">Janet E. Olson</name><affiliation><nlm:affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hallberg, Emily" sort="Hallberg, Emily" uniqKey="Hallberg E" first="Emily" last="Hallberg">Emily Hallberg</name><affiliation><nlm:affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G" last="Giles">Graham G. Giles</name><affiliation><nlm:affiliation>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L" last="Milne">Roger L. Milne</name><affiliation><nlm:affiliation>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.</nlm:affiliation></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:affiliation>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, M5B 1W8, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Glendon, Gord" sort="Glendon, Gord" uniqKey="Glendon G" first="Gord" last="Glendon">Gord Glendon</name><affiliation><nlm:affiliation>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Blows, Fiona" sort="Blows, Fiona" uniqKey="Blows F" first="Fiona" last="Blows">Fiona Blows</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Shah, Mitul" sort="Shah, Mitul" uniqKey="Shah M" first="Mitul" last="Shah">Mitul Shah</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Qin" sort="Wang, Qin" uniqKey="Wang Q" first="Qin" last="Wang">Qin Wang</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Dennis, Joe" sort="Dennis, Joe" uniqKey="Dennis J" first="Joe" last="Dennis">Joe Dennis</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Michailidou, Kyriaki" sort="Michailidou, Kyriaki" uniqKey="Michailidou K" first="Kyriaki" last="Michailidou">Kyriaki Michailidou</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683, Nicosia, Cyprus.</nlm:affiliation></affiliation></author><author><name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bolla, Manjeet K" sort="Bolla, Manjeet K" uniqKey="Bolla M" first="Manjeet K" last="Bolla">Manjeet K. Bolla</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></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:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F" last="Easton">Douglas F. Easton</name><affiliation><nlm:affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</nlm:affiliation></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:affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tavtigian, Sean" sort="Tavtigian, Sean" uniqKey="Tavtigian S" first="Sean" last="Tavtigian">Sean Tavtigian</name><affiliation><nlm:affiliation>Department of Oncological Sciences.</nlm:affiliation></affiliation></author><author><name sortKey="Vreeswijk, Maaike P" sort="Vreeswijk, Maaike P" uniqKey="Vreeswijk M" first="Maaike P" last="Vreeswijk">Maaike P. Vreeswijk</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Parsons, Michael" sort="Parsons, Michael" uniqKey="Parsons M" first="Michael" last="Parsons">Michael Parsons</name><affiliation><nlm:affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Meeks, Huong D" sort="Meeks, Huong D" uniqKey="Meeks H" first="Huong D" last="Meeks">Huong D. Meeks</name><affiliation><nlm:affiliation>Department of Oncological Sciences.</nlm:affiliation></affiliation></author><author><name sortKey="Martins, Alexandra" sort="Martins, Alexandra" uniqKey="Martins A" first="Alexandra" last="Martins">Alexandra Martins</name><affiliation><nlm:affiliation>Inserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E" last="Goldgar">David E. Goldgar</name><affiliation><nlm:affiliation>Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name><affiliation><nlm:affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia amanda.spurdle@qimr.edu.au mhoya@hotmail.com.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Alternative Splicing (genetics)</term><term>BRCA1 Protein (genetics)</term><term>Breast Neoplasms (genetics)</term><term>Breast Neoplasms (pathology)</term><term>DNA Mutational Analysis</term><term>Exons (genetics)</term><term>Female</term><term>Gene Expression Regulation, Neoplastic</term><term>Humans</term><term>Middle Aged</term><term>Mutation (genetics)</term><term>Ovarian Neoplasms (genetics)</term><term>Ovarian Neoplasms (pathology)</term><term>RNA Splice Sites (genetics)</term><term>RNA Splicing (genetics)</term><term>Tumor Suppressor Proteins (genetics)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>BRCA1 Protein</term><term>RNA Splice Sites</term><term>Tumor Suppressor Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Alternative Splicing</term><term>Breast Neoplasms</term><term>Exons</term><term>Mutation</term><term>Ovarian Neoplasms</term><term>RNA Splicing</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Breast Neoplasms</term><term>Ovarian Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>DNA Mutational Analysis</term><term>Female</term><term>Gene Expression Regulation, Neoplastic</term><term>Humans</term><term>Middle Aged</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10(-8) Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27008870</PMID><DateCreated><Year>2016</Year><Month>04</Month><Day>23</Day></DateCreated><DateCompleted><Year>2017</Year><Month>09</Month><Day>25</Day></DateCompleted><DateRevised><Year>2017</Year><Month>09</Month><Day>25</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2083</ISSN><JournalIssue CitedMedium="Internet"><Volume>25</Volume><Issue>11</Issue><PubDate><Year>2016</Year><Month>Jun</Month><Day>01</Day></PubDate></JournalIssue><Title>Human molecular genetics</Title><ISOAbbreviation>Hum. Mol. Genet.</ISOAbbreviation></Journal><ArticleTitle>Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.</ArticleTitle><Pagination><MedlinePgn>2256-2268</MedlinePgn></Pagination><Abstract><AbstractText>A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10(-8) Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.</AbstractText><CopyrightInformation>© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>de la Hoya</LastName><ForeName>Miguel</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain amanda.spurdle@qimr.edu.au mhoya@hotmail.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Soukarieh</LastName><ForeName>Omar</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Inserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>López-Perolio</LastName><ForeName>Irene</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vega</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Fundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Walker</LastName><ForeName>Logan C</ForeName><Initials>LC</Initials><AffiliationInfo><Affiliation>Department of Pathology, University of Otago, Christchurch 8140, New Zealand.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Ierland</LastName><ForeName>Yvette</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baralle</LastName><ForeName>Diana</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Human Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Santamariña</LastName><ForeName>Marta</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>CIBERER, Grupo de Medicina Xenómica-USC, Universidade de Santiago de Compostela, Fundacion Galega de Medicina Xenómica (SERGAS), Santiago de Compostela 15706, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lattimore</LastName><ForeName>Vanessa</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Department of Pathology, University of Otago, Christchurch 8140, New Zealand.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wijnen</LastName><ForeName>Juul</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Whiley</LastName><ForeName>Philip</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blanco</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Fundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Raponi</LastName><ForeName>Michela</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Human Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hauke</LastName><ForeName>Jan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wappenschmidt</LastName><ForeName>Barbara</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Becker</LastName><ForeName>Alexandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hansen</LastName><ForeName>Thomas V O</ForeName><Initials>TV</Initials><AffiliationInfo><Affiliation>Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen DK-2100, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Behar</LastName><ForeName>Raquel</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Investigators</LastName><ForeName>KConFaB</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Peter MacCallum Cancer Center, University of Melbourne, Melbourne, VIC 3002, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Niederacher</LastName><ForeName>Diether</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arnold</LastName><ForeName>Norbert</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel 24105, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dworniczak</LastName><ForeName>Bernd</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, University of Münster, Münster 48149, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steinemann</LastName><ForeName>Doris</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Faust</LastName><ForeName>Ulrike</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen 72076, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rubinstein</LastName><ForeName>Wendy</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>National Institutes of Health, Bethesda, MD 20892-2152, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hulick</LastName><ForeName>Peter J</ForeName><Initials>PJ</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, NorthShore University Health System, University of Chicago Pritzker School of Medicine, Evanston, IL 60201, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Houdayer</LastName><ForeName>Claude</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Service de Génétique, Department de Biologie des Tumeurs, Institut Curie and INSERM U830, Centre de Recherche de l'Institut Curie, Paris, and Universite Paris Descartes, Sorbonne Paris Cite, Paris 75248, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Caputo</LastName><ForeName>Sandrine M</ForeName><Initials>SM</Initials><AffiliationInfo><Affiliation>Service de Génétique, Department de Biologie des Tumeurs, Institut Curie, Paris 75248, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Castera</LastName><ForeName>Laurent</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Centre Francois Baclesse, Laboratoire de Biologie et de Genetique du Cancer, 14076 Caen, Paris 75248, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pesaran</LastName><ForeName>Tina</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Ambry Genetics, Aliso Viejo, CA 92656, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chao</LastName><ForeName>Elizabeth</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Ambry Genetics, Aliso Viejo, CA 92656, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brewer</LastName><ForeName>Carole</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Southey</LastName><ForeName>Melissa C</ForeName><Initials>MC</Initials><AffiliationInfo><Affiliation>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Asperen</LastName><ForeName>Christi J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singer</LastName><ForeName>Christian F</ForeName><Initials>CF</Initials><AffiliationInfo><Affiliation>Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sullivan</LastName><ForeName>Jan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Genetic Health Service NZ, South Island Hub, Christchurch Hospital, Christchurch 8140, New Zealand.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Poplawski</LastName><ForeName>Nicola</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Adult Genetics Unit, South Australian Clinical Genetics Service, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5067, Australia University Department of Paediatrics, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mai</LastName><ForeName>Phuong</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Clinical Genetics Branch, DCEG, NCI, NIH, Bethesda, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peto</LastName><ForeName>Julian</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Johnson</LastName><ForeName>Nichola</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Burwinkel</LastName><ForeName>Barbara</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Surowy</LastName><ForeName>Harald</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bojesen</LastName><ForeName>Stig E</ForeName><Initials>SE</Initials><AffiliationInfo><Affiliation>Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen 2730, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1165, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Flyger</LastName><ForeName>Henrik</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lindblom</LastName><ForeName>Annika</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Margolin</LastName><ForeName>Sara</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Oncology Pathology, Karolinska Institutet, Stockholm SE-171 77, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chang-Claude</LastName><ForeName>Jenny</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rudolph</LastName><ForeName>Anja</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Radice</LastName><ForeName>Paolo</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Unit of "Molecular bases of genetic risk and genetic testing", Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20139, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Galastri</LastName><ForeName>Laura</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Associazione Volontari Italiani Sangue (AVIS) comunale di Milano, Milano 20139, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Olson</LastName><ForeName>Janet E</ForeName><Initials>JE</Initials><AffiliationInfo><Affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hallberg</LastName><ForeName>Emily</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Giles</LastName><ForeName>Graham G</ForeName><Initials>GG</Initials><AffiliationInfo><Affiliation>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Milne</LastName><ForeName>Roger L</ForeName><Initials>RL</Initials><AffiliationInfo><Affiliation>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Andrulis</LastName><ForeName>Irene L</ForeName><Initials>IL</Initials><AffiliationInfo><Affiliation>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, M5B 1W8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Glendon</LastName><ForeName>Gord</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hall</LastName><ForeName>Per</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Czene</LastName><ForeName>Kamila</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blows</LastName><ForeName>Fiona</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shah</LastName><ForeName>Mitul</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Qin</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dennis</LastName><ForeName>Joe</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Michailidou</LastName><ForeName>Kyriaki</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683, Nicosia, Cyprus.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McGuffog</LastName><ForeName>Lesley</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bolla</LastName><ForeName>Manjeet K</ForeName><Initials>MK</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Antoniou</LastName><ForeName>Antonis C</ForeName><Initials>AC</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Easton</LastName><ForeName>Douglas F</ForeName><Initials>DF</Initials><AffiliationInfo><Affiliation>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Couch</LastName><ForeName>Fergus J</ForeName><Initials>FJ</Initials><AffiliationInfo><Affiliation>Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tavtigian</LastName><ForeName>Sean</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Oncological Sciences.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vreeswijk</LastName><ForeName>Maaike P</ForeName><Initials>MP</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Parsons</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Meeks</LastName><ForeName>Huong D</ForeName><Initials>HD</Initials><AffiliationInfo><Affiliation>Department of Oncological Sciences.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martins</LastName><ForeName>Alexandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Inserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Goldgar</LastName><ForeName>David E</ForeName><Initials>DE</Initials><AffiliationInfo><Affiliation>Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Spurdle</LastName><ForeName>Amanda B</ForeName><Initials>AB</Initials><AffiliationInfo><Affiliation>Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia amanda.spurdle@qimr.edu.au mhoya@hotmail.com.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>11174</GrantID><Agency>Cancer Research UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>U01 CA116167</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA128978</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P50 CA116201</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>10118</GrantID><Agency>Cancer Research UK</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>03</Month><Day>23</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Hum Mol Genet</MedlineTA><NlmUniqueID>9208958</NlmUniqueID><ISSNLinking>0964-6906</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019313">BRCA1 Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D022821">RNA Splice Sites</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D025521">Tumor Suppressor Proteins</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Eur J Hum Genet. 2014 Dec;22(12):1362-8</RefSource><PMID Version="1">24667779</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Crit Rev Oncol Hematol. 2007 Feb;61(2):153-61</RefSource><PMID Version="1">17064931</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Hum Mol Genet. 2014 Jul 15;23(14):3666-80</RefSource><PMID 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PubStatus="received"><Year>2015</Year><Month>11</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>03</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>10</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>9</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>3</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27008870</ArticleId><ArticleId IdType="pii">ddw094</ArticleId><ArticleId IdType="doi">10.1093/hmg/ddw094</ArticleId><ArticleId IdType="pmc">PMC5081057</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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