BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk
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Auteurs : Amanda B. Spurdle [Australie] ; Phillip J. Whiley [Australie] ; Bryony Thompson [Australie] ; Bingjian Feng [États-Unis] ; Sue Healey [Australie] ; Melissa A. Brown [Australie] ; Christopher Pettigrew [Australie] ; Christi J. Van Asperen [Pays-Bas] ; Margreet G E M. Ausems [Pays-Bas] ; Anna A. Kattentidt-Mouravieva [Pays-Bas] ; Ans M W. Van Den Ouweland [Pays-Bas] ; Annika Lindblom [Suède] ; Maritta H. Pigg [Suède] ; Rita K. Schmutzler [Allemagne] ; Christoph Engel [Allemagne] ; Alfons Meindl [Allemagne] ; Sandrine Caputo [France] ; Olga M. Sinilnikova [France] ; Rosette Lidereau [France] ; Fergus J. Couch [États-Unis] ; Lucia Guidugli [États-Unis] ; Thomas Van Overeem Hansen [Danemark] ; Mads Thomassen [Danemark] ; Diana M. Eccles [Royaume-Uni] ; Kathy Tucker [Australie] ; Javier Benitez [Espagne] ; Susan M. Domchek [États-Unis] ; Amanda E. Toland [États-Unis] ; Elizabeth J. Van Rensburg [Afrique du Sud] ; Barbara Wappenschmidt [Allemagne] ; Ke Borg [Suède] ; Maaike P G. Vreeswijk [Pays-Bas] ; David E. Goldgar [États-Unis]Source :
- Journal of medical genetics [ 0022-2593 ] ; 2012.
Abstract
Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes
Measures of genetic risk (report of family history, segregation) were assessed for 68
Comparison of
Our results provide substantial evidence that the
Url:
DOI: 10.1136/jmedgenet-2012-101037
PubMed: 22889855
PubMed Central: 3810416
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Spurdle</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Queensland, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Whiley, Phillip J" sort="Whiley, Phillip J" uniqKey="Whiley P" first="Phillip J" last="Whiley">Phillip J. Whiley</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Thompson, Bryony" sort="Thompson, Bryony" uniqKey="Thompson B" first="Bryony" last="Thompson">Bryony Thompson</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Queensland, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Feng, Bingjian" sort="Feng, Bingjian" uniqKey="Feng B" first="Bingjian" last="Feng">Bingjian Feng</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</wicri:regionArea></affiliation></author><author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Brown, Melissa A" sort="Brown, Melissa A" uniqKey="Brown M" first="Melissa A" last="Brown">Melissa A. Brown</name><affiliation wicri:level="1"><nlm:aff id="A4">School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Pettigrew, Christopher" sort="Pettigrew, Christopher" uniqKey="Pettigrew C" first="Christopher" last="Pettigrew">Christopher Pettigrew</name><affiliation wicri:level="1"><nlm:aff id="A4">School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A6">Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Ausems, Margreet G E M" sort="Ausems, Margreet G E M" uniqKey="Ausems M" first="Margreet G E M" last="Ausems">Margreet G E M. Ausems</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Genetics, University Medical Center Utrecht, Utrecht</wicri:regionArea></affiliation></author><author><name sortKey="Kattentidt Mouravieva, Anna A" sort="Kattentidt Mouravieva, Anna A" uniqKey="Kattentidt Mouravieva A" first="Anna A" last="Kattentidt-Mouravieva">Anna A. Kattentidt-Mouravieva</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Van Den Ouweland, Ans M W" sort="Van Den Ouweland, Ans M W" uniqKey="Van Den Ouweland A" first="Ans M W" last="Van Den Ouweland">Ans M W. Van Den Ouweland</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Lindblom, Annika" sort="Lindblom, Annika" uniqKey="Lindblom A" first="Annika" last="Lindblom">Annika Lindblom</name><affiliation wicri:level="1"><nlm:aff id="A11">Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Pigg, Maritta H" sort="Pigg, Maritta H" uniqKey="Pigg M" first="Maritta H" last="Pigg">Maritta H. Pigg</name><affiliation wicri:level="1"><nlm:aff id="A12">Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala</wicri:regionArea></affiliation></author><author><name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K" last="Schmutzler">Rita K. Schmutzler</name><affiliation wicri:level="1"><nlm:aff id="A13">Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne</wicri:regionArea></affiliation></author><author><name sortKey="Engel, Christoph" sort="Engel, Christoph" uniqKey="Engel C" first="Christoph" last="Engel">Christoph Engel</name><affiliation wicri:level="1"><nlm:aff id="A14">Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig</wicri:regionArea></affiliation></author><author><name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name><affiliation wicri:level="1"><nlm:aff id="A15">Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Technical University of Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Caputo, Sandrine" sort="Caputo, Sandrine" uniqKey="Caputo S" first="Sandrine" last="Caputo">Sandrine Caputo</name><affiliation wicri:level="1"><nlm:aff id="A16">Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud</wicri:regionArea></affiliation></author><author><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M" last="Sinilnikova">Olga M. Sinilnikova</name><affiliation wicri:level="1"><nlm:aff id="A17">Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A18">INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon</wicri:regionArea></affiliation></author><author><name sortKey="Lidereau, Rosette" sort="Lidereau, Rosette" uniqKey="Lidereau R" first="Rosette" last="Lidereau">Rosette Lidereau</name><affiliation wicri:level="1"><nlm:aff id="A16">Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A20">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota</wicri:regionArea></affiliation></author><author><name sortKey="Guidugli, Lucia" sort="Guidugli, Lucia" uniqKey="Guidugli L" first="Lucia" last="Guidugli">Lucia Guidugli</name><affiliation wicri:level="1"><nlm:aff id="A20">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota</wicri:regionArea></affiliation></author><author><name sortKey="Hansen, Thomas Van Overeem" sort="Hansen, Thomas Van Overeem" uniqKey="Hansen T" first="Thomas Van Overeem" last="Hansen">Thomas Van Overeem Hansen</name><affiliation wicri:level="1"><nlm:aff id="A21">Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen</wicri:regionArea></affiliation></author><author><name sortKey="Thomassen, Mads" sort="Thomassen, Mads" uniqKey="Thomassen M" first="Mads" last="Thomassen">Mads Thomassen</name><affiliation wicri:level="1"><nlm:aff id="A22">Department of Clinical Genetics, Odense University Hospital, Odense, Denmark</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Clinical Genetics, Odense University Hospital, Odense</wicri:regionArea></affiliation></author><author><name sortKey="Eccles, Diana M" sort="Eccles, Diana M" uniqKey="Eccles D" first="Diana M" last="Eccles">Diana M. Eccles</name><affiliation wicri:level="1"><nlm:aff id="A23">Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton</wicri:regionArea></affiliation></author><author><name sortKey="Tucker, Kathy" sort="Tucker, Kathy" uniqKey="Tucker K" first="Kathy" last="Tucker">Kathy Tucker</name><affiliation wicri:level="1"><nlm:aff id="A24">Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick</wicri:regionArea></affiliation></author><author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benitez">Javier Benitez</name><affiliation wicri:level="1"><nlm:aff id="A25">Spanish National Cancer Centre, Madrid, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Spanish National Cancer Centre, Madrid</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A26">Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Toland, Amanda E" sort="Toland, Amanda E" uniqKey="Toland A" first="Amanda E" last="Toland">Amanda E. Toland</name><affiliation wicri:level="1"><nlm:aff id="A27">Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A28">Department of Genetics, University of Pretoria, Hatfield, South Africa</nlm:aff><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Department of Genetics, University of Pretoria, Hatfield</wicri:regionArea></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation wicri:level="1"><nlm:aff id="A13">Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne</wicri:regionArea></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation wicri:level="1"><nlm:aff id="A29">Åke Borg, Department of Oncology, Lund University, Lund, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Åke Borg, Department of Oncology, Lund University, Lund</wicri:regionArea></affiliation></author><author><name sortKey="Vreeswijk, Maaike P G" sort="Vreeswijk, Maaike P G" uniqKey="Vreeswijk M" first="Maaike P G" last="Vreeswijk">Maaike P G. Vreeswijk</name><affiliation wicri:level="1"><nlm:aff id="A30">Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A3">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A31">Huntsman Cancer Institute, Salt Lake City, Utah, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Huntsman Cancer Institute, Salt Lake City, Utah</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22889855</idno><idno type="pmc">3810416</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810416</idno><idno type="RBID">PMC:3810416</idno><idno type="doi">10.1136/jmedgenet-2012-101037</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001F18</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001F18</idno><idno type="wicri:Area/Pmc/Curation">001D74</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001D74</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk</title><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Queensland, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Whiley, Phillip J" sort="Whiley, Phillip J" uniqKey="Whiley P" first="Phillip J" last="Whiley">Phillip J. Whiley</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Thompson, Bryony" sort="Thompson, Bryony" uniqKey="Thompson B" first="Bryony" last="Thompson">Bryony Thompson</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Queensland, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Feng, Bingjian" sort="Feng, Bingjian" uniqKey="Feng B" first="Bingjian" last="Feng">Bingjian Feng</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</wicri:regionArea></affiliation></author><author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name><affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Brown, Melissa A" sort="Brown, Melissa A" uniqKey="Brown M" first="Melissa A" last="Brown">Melissa A. Brown</name><affiliation wicri:level="1"><nlm:aff id="A4">School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland</wicri:regionArea></affiliation></author><author><name sortKey="Pettigrew, Christopher" sort="Pettigrew, Christopher" uniqKey="Pettigrew C" first="Christopher" last="Pettigrew">Christopher Pettigrew</name><affiliation wicri:level="1"><nlm:aff id="A4">School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A6">Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Ausems, Margreet G E M" sort="Ausems, Margreet G E M" uniqKey="Ausems M" first="Margreet G E M" last="Ausems">Margreet G E M. Ausems</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Genetics, University Medical Center Utrecht, Utrecht</wicri:regionArea></affiliation></author><author><name sortKey="Kattentidt Mouravieva, Anna A" sort="Kattentidt Mouravieva, Anna A" uniqKey="Kattentidt Mouravieva A" first="Anna A" last="Kattentidt-Mouravieva">Anna A. Kattentidt-Mouravieva</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Van Den Ouweland, Ans M W" sort="Van Den Ouweland, Ans M W" uniqKey="Van Den Ouweland A" first="Ans M W" last="Van Den Ouweland">Ans M W. Van Den Ouweland</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Lindblom, Annika" sort="Lindblom, Annika" uniqKey="Lindblom A" first="Annika" last="Lindblom">Annika Lindblom</name><affiliation wicri:level="1"><nlm:aff id="A11">Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Pigg, Maritta H" sort="Pigg, Maritta H" uniqKey="Pigg M" first="Maritta H" last="Pigg">Maritta H. Pigg</name><affiliation wicri:level="1"><nlm:aff id="A12">Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala</wicri:regionArea></affiliation></author><author><name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K" last="Schmutzler">Rita K. Schmutzler</name><affiliation wicri:level="1"><nlm:aff id="A13">Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne</wicri:regionArea></affiliation></author><author><name sortKey="Engel, Christoph" sort="Engel, Christoph" uniqKey="Engel C" first="Christoph" last="Engel">Christoph Engel</name><affiliation wicri:level="1"><nlm:aff id="A14">Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig</wicri:regionArea></affiliation></author><author><name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name><affiliation wicri:level="1"><nlm:aff id="A15">Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Technical University of Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Caputo, Sandrine" sort="Caputo, Sandrine" uniqKey="Caputo S" first="Sandrine" last="Caputo">Sandrine Caputo</name><affiliation wicri:level="1"><nlm:aff id="A16">Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud</wicri:regionArea></affiliation></author><author><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M" last="Sinilnikova">Olga M. Sinilnikova</name><affiliation wicri:level="1"><nlm:aff id="A17">Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A18">INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon</wicri:regionArea></affiliation></author><author><name sortKey="Lidereau, Rosette" sort="Lidereau, Rosette" uniqKey="Lidereau R" first="Rosette" last="Lidereau">Rosette Lidereau</name><affiliation wicri:level="1"><nlm:aff id="A16">Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A20">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota</wicri:regionArea></affiliation></author><author><name sortKey="Guidugli, Lucia" sort="Guidugli, Lucia" uniqKey="Guidugli L" first="Lucia" last="Guidugli">Lucia Guidugli</name><affiliation wicri:level="1"><nlm:aff id="A20">Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota</wicri:regionArea></affiliation></author><author><name sortKey="Hansen, Thomas Van Overeem" sort="Hansen, Thomas Van Overeem" uniqKey="Hansen T" first="Thomas Van Overeem" last="Hansen">Thomas Van Overeem Hansen</name><affiliation wicri:level="1"><nlm:aff id="A21">Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen</wicri:regionArea></affiliation></author><author><name sortKey="Thomassen, Mads" sort="Thomassen, Mads" uniqKey="Thomassen M" first="Mads" last="Thomassen">Mads Thomassen</name><affiliation wicri:level="1"><nlm:aff id="A22">Department of Clinical Genetics, Odense University Hospital, Odense, Denmark</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Clinical Genetics, Odense University Hospital, Odense</wicri:regionArea></affiliation></author><author><name sortKey="Eccles, Diana M" sort="Eccles, Diana M" uniqKey="Eccles D" first="Diana M" last="Eccles">Diana M. Eccles</name><affiliation wicri:level="1"><nlm:aff id="A23">Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton</wicri:regionArea></affiliation></author><author><name sortKey="Tucker, Kathy" sort="Tucker, Kathy" uniqKey="Tucker K" first="Kathy" last="Tucker">Kathy Tucker</name><affiliation wicri:level="1"><nlm:aff id="A24">Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick</wicri:regionArea></affiliation></author><author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benitez">Javier Benitez</name><affiliation wicri:level="1"><nlm:aff id="A25">Spanish National Cancer Centre, Madrid, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Spanish National Cancer Centre, Madrid</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A26">Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Toland, Amanda E" sort="Toland, Amanda E" uniqKey="Toland A" first="Amanda E" last="Toland">Amanda E. Toland</name><affiliation wicri:level="1"><nlm:aff id="A27">Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A28">Department of Genetics, University of Pretoria, Hatfield, South Africa</nlm:aff><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Department of Genetics, University of Pretoria, Hatfield</wicri:regionArea></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation wicri:level="1"><nlm:aff id="A13">Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne</wicri:regionArea></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation wicri:level="1"><nlm:aff id="A29">Åke Borg, Department of Oncology, Lund University, Lund, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Åke Borg, Department of Oncology, Lund University, Lund</wicri:regionArea></affiliation></author><author><name sortKey="Vreeswijk, Maaike P G" sort="Vreeswijk, Maaike P G" uniqKey="Vreeswijk M" first="Maaike P G" last="Vreeswijk">Maaike P G. Vreeswijk</name><affiliation wicri:level="1"><nlm:aff id="A30">Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden</wicri:regionArea></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 wicri:level="1"><nlm:aff id="A3">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A31">Huntsman Cancer Institute, Salt Lake City, Utah, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Huntsman Cancer Institute, Salt Lake City, Utah</wicri:regionArea></affiliation></author></analytic><series><title level="j">Journal of medical genetics</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title><p id="P2">Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes <italic>BRCA1</italic> and <italic>BRCA2</italic> is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.</p></sec><sec id="S2"><title>Methods</title><p id="P3">Measures of genetic risk (report of family history, segregation) were assessed for 68 <italic>BRCA1</italic> c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic <italic>BRCA1</italic> c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no <italic>BRCA1</italic> pathogenic mutation (BRCA-X).</p></sec><sec id="S3"><title>Results</title><p id="P4">Comparison of <italic>BRCA1</italic> carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that <italic>BRCA1</italic> c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘<italic>BRCA1</italic>-like’ than <italic>BRCA1</italic> c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘<italic>BRCA1</italic>-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that <italic>BRCA1</italic> c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating <italic>BRCA1</italic> mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%.</p></sec><sec id="S4"><title>Conclusions</title><p id="P5">Our results provide substantial evidence that the <italic>BRCA1</italic> c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">2985087R</journal-id><journal-id journal-id-type="pubmed-jr-id">4945</journal-id><journal-id journal-id-type="nlm-ta">J Med Genet</journal-id><journal-id journal-id-type="iso-abbrev">J. Med. Genet.</journal-id><journal-title-group><journal-title>Journal of medical genetics</journal-title></journal-title-group><issn pub-type="ppub">0022-2593</issn><issn pub-type="epub">1468-6244</issn></journal-meta><article-meta><article-id pub-id-type="pmid">22889855</article-id><article-id pub-id-type="pmc">3810416</article-id><article-id pub-id-type="doi">10.1136/jmedgenet-2012-101037</article-id><article-id pub-id-type="manuscript">NIHMS498935</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Spurdle</surname><given-names>Amanda B</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Whiley</surname><given-names>Phillip J</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Thompson</surname><given-names>Bryony</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Bingjian</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Healey</surname><given-names>Sue</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Melissa A</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Pettigrew</surname><given-names>Christopher</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>kConFab</surname><given-names></given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Van Asperen</surname><given-names>Christi J</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Ausems</surname><given-names>Margreet G E M</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Kattentidt-Mouravieva</surname><given-names>Anna A</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>van den Ouweland</surname><given-names>Ans M W</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><collab>Dutch Belgium UV Consortium</collab><xref ref-type="author-notes" rid="FN1">9</xref><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Lindblom</surname><given-names>Annika</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Pigg</surname><given-names>Maritta H</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Schmutzler</surname><given-names>Rita K</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Engel</surname><given-names>Christoph</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Meindl</surname><given-names>Alfons</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><collab>German Consortium of Hereditary Breast and Ovarian Cancer</collab><xref ref-type="author-notes" rid="FN1">9</xref><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Caputo</surname><given-names>Sandrine</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Sinilnikova</surname><given-names>Olga M</given-names></name><xref ref-type="aff" rid="A17">17</xref><xref ref-type="aff" rid="A18">18</xref></contrib><contrib contrib-type="author"><name><surname>Lidereau</surname><given-names>Rosette</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><collab>French COVAR group collaborators</collab><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Couch</surname><given-names>Fergus J</given-names></name><xref ref-type="aff" rid="A20">20</xref></contrib><contrib contrib-type="author"><name><surname>Guidugli</surname><given-names>Lucia</given-names></name><xref ref-type="aff" rid="A20">20</xref></contrib><contrib contrib-type="author"><name><surname>Hansen</surname><given-names>Thomas van Overeem</given-names></name><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Thomassen</surname><given-names>Mads</given-names></name><xref ref-type="aff" rid="A22">22</xref></contrib><contrib contrib-type="author"><name><surname>Eccles</surname><given-names>Diana M</given-names></name><xref ref-type="aff" rid="A23">23</xref></contrib><contrib contrib-type="author"><name><surname>Tucker</surname><given-names>Kathy</given-names></name><xref ref-type="aff" rid="A24">24</xref></contrib><contrib contrib-type="author"><name><surname>Benitez</surname><given-names>Javier</given-names></name><xref ref-type="aff" rid="A25">25</xref></contrib><contrib contrib-type="author"><name><surname>Domchek</surname><given-names>Susan M</given-names></name><xref ref-type="aff" rid="A26">26</xref></contrib><contrib contrib-type="author"><name><surname>Toland</surname><given-names>Amanda E</given-names></name><xref ref-type="aff" rid="A27">27</xref></contrib><contrib contrib-type="author"><name><surname>Van Rensburg</surname><given-names>Elizabeth J</given-names></name><xref ref-type="aff" rid="A28">28</xref></contrib><contrib contrib-type="author"><name><surname>Wappenschmidt</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Borg</surname><given-names>Åke</given-names></name><xref ref-type="aff" rid="A29">29</xref></contrib><contrib contrib-type="author"><name><surname>Vreeswijk</surname><given-names>Maaike P G</given-names></name><xref ref-type="aff" rid="A30">30</xref></contrib><contrib contrib-type="author"><name><surname>Goldgar</surname><given-names>David E</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A31">31</xref><on-behalf-of>on behalf of the ENIGMA Consortium</on-behalf-of><xref ref-type="author-notes" rid="FN1">9</xref></contrib></contrib-group><aff id="A1"><label>1</label>Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia</aff><aff id="A2"><label>2</label>School of Medicine, University of Queensland, Brisbane, Queensland, Australia</aff><aff id="A3"><label>3</label>Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA</aff><aff id="A4"><label>4</label>School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia</aff><aff id="A5"><label>5</label>Peter MacCallum Cancer Institute, Melbourne, Victoria 3000, Australia</aff><aff id="A6"><label>6</label>Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</aff><aff id="A7"><label>7</label>Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands</aff><aff id="A8"><label>8</label>Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands</aff><aff id="A10"><label>10</label>Dutch Belgium UV Consortium, Co-ordinator F.B. Hogervorst, The Netherlands Cancer Institute, Amsterdam, The Netherlands</aff><aff id="A11"><label>11</label>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden</aff><aff id="A12"><label>12</label>Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden</aff><aff id="A13"><label>13</label>Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany</aff><aff id="A14"><label>14</label>Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany</aff><aff id="A15"><label>15</label>Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany</aff><aff id="A16"><label>16</label>Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud, France</aff><aff id="A17"><label>17</label>Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon, France</aff><aff id="A18"><label>18</label>INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France</aff><aff id="A19"><label>19</label>French COVAR group collaborators co-ordinator Rosette Lidereau, Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM—Saint-Cloud, France</aff><aff id="A20"><label>20</label>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA</aff><aff id="A21"><label>21</label>Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark</aff><aff id="A22"><label>22</label>Department of Clinical Genetics, Odense University Hospital, Odense, Denmark</aff><aff id="A23"><label>23</label>Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton, UK</aff><aff id="A24"><label>24</label>Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Australia</aff><aff id="A25"><label>25</label>Spanish National Cancer Centre, Madrid, Spain</aff><aff id="A26"><label>26</label>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA</aff><aff id="A27"><label>27</label>Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA</aff><aff id="A28"><label>28</label>Department of Genetics, University of Pretoria, Hatfield, South Africa</aff><aff id="A29"><label>29</label>Åke Borg, Department of Oncology, Lund University, Lund, Sweden</aff><aff id="A30"><label>30</label>Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</aff><aff id="A31"><label>31</label>Huntsman Cancer Institute, Salt Lake City, Utah, USA</aff><author-notes><corresp id="cor1"><bold>Correspondence to</bold>: Dr Amanda B Spurdle, Division of Genetics and Population Health, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4006, Australia; <email>Amanda.Spurdle@qimr.edu.au</email>; Professor David E Goldgar, Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; <email>david.goldgar@hsc.utah.edu</email></corresp><fn id="FN1"><label>9</label><p id="P1">See <xref ref-type="supplementary-material" rid="SD1">Appendix</xref> for full list of ENIGMA collaborators contributing to this study, operating within and outside of country consortia</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>10</day><month>9</month><year>2013</year></pub-date><pub-date pub-type="ppub"><month>8</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>28</day><month>10</month><year>2013</year></pub-date><volume>49</volume><issue>8</issue><elocation-id>10.1136/jmedgenet-2012-101037</elocation-id><abstract><sec id="S1"><title>Background</title><p id="P2">Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes <italic>BRCA1</italic> and <italic>BRCA2</italic> is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.</p></sec><sec id="S2"><title>Methods</title><p id="P3">Measures of genetic risk (report of family history, segregation) were assessed for 68 <italic>BRCA1</italic> c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic <italic>BRCA1</italic> c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no <italic>BRCA1</italic> pathogenic mutation (BRCA-X).</p></sec><sec id="S3"><title>Results</title><p id="P4">Comparison of <italic>BRCA1</italic> carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that <italic>BRCA1</italic> c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘<italic>BRCA1</italic>-like’ than <italic>BRCA1</italic> c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘<italic>BRCA1</italic>-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that <italic>BRCA1</italic> c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating <italic>BRCA1</italic> mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%.</p></sec><sec id="S4"><title>Conclusions</title><p id="P5">Our results provide substantial evidence that the <italic>BRCA1</italic> c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.</p></sec></abstract><funding-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source><award-id>R01 CA116167 || CA</award-id></award-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source><award-id>P50 CA116201 || CA</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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