IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia2Center for Clinical Epidemiology and Biostatistics Perelman School of Medicine at the University of Pennsylvania Philadelphia

Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia6Department of Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia

Academic Unit of Clinical and Molecular Oncology Trinity College Dublin and St James's Hospital Dublin Eire

AO Città della Salute e della Scienza Turin Italy

Canada Research Chair in Oncogenetics Cancer Genomics Laboratory Centre Hospitalier Universitaire de Québec Research Center Quebec City Quebec Canada149Laval University Quebec City Quebec Canada

Cancer Bioimmunotherapy Unit Centro di Riferimento Oncologico IRCCSCRO Aviano National Cancer Institute Aviano Italy

Cancer Research Initiatives Foundation Sime Darby Medical Centre Subang Jaya Malaysia176Department of Surgery Faculty of Medicine University Malaya Cancer Research Institute University Malaya Kuala Lumpur Malaysia

Cancer Risk Program Helen Diller Family Cancer Center University of California San Francisco

Center for Clinical Cancer Genetics and Global Health University of Chicago Medical Center Chicago Illinois

Center for Clinical Epidemiology and Biostatistics Perelman School of Medicine at the University of Pennsylvania Philadelphia

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology Medical Faculty University of Cologne and University Hospital Cologne Cologne Germany

Center for Medical Genetics Ghent University Ghent Belgium

Centre de Recherche en Cancérologie de Lyon UMR Inserm Centre Léon Bérard Lyon France

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Centre of Familial Breast and Ovarian Cancer Department of Medical Genetics Institute of Human Genetics University of Würzburg Würzburg Germany

Clinical Cancer Genetics City of Hope Clinical Cancer Genetics Community Research Network Duarte California

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Rockville Maryland

Clinical Genetics Department St Georges Hospital University of London United Kingdom

Clinical Genetics Service Cancer Biology and Genetics Program Memorial Sloan Kettering Cancer Center New York New York

Clinical Genetics Service Memorial Sloan Kettering Cancer Center New York New York

Cogentech Cancer Genetic Test Laboratory Milan Italy60IFOM Fondazione Istituto FIRC di Oncologia Molecolare Milan Italy

Dana Farber Cancer Institute Boston Massachusetts

Département Oncologie Génétique Prévention et Dépistage INSERM CIC P9502 Institut Paoli Calmettes Université d'Aix Marseille 2 Marseille France

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute and MF MU Brno Czech Republic

Department of Clinical Genetics Aarhus University Hospital Aarhus N Denmark

Department of Clinical Genetics Academic Medical Center Amsterdam The Netherlands

Department of Clinical Genetics and GROW School for Oncology and Developmental Biology MUMC Maastricht The Netherlands

Department of Clinical Genetics Family Cancer Clinic Erasmus University Medical Center Rotterdam The Netherlands

Department of Clinical Genetics Helsinki University Central Hospital Helsinki Finland

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Odense University Hospital Odense C Denmark

Department of Clinical Genetics Royal Devon and Exeter Hospital Exeter United Kingdom

Department of Clinical Genetics Vejle Hospital Vejle Denmark

Department of Clinical Genetics VU University Medical Centre Amsterdam The Netherlands

Department of Dermatology University of Utah School of Medicine Salt Lake City

Department of Epidemiology Cancer Prevention Institute of California Fremont

Department of Epidemiology Columbia University New York New York

Department of Experimental Oncology Istituto Europeo di Oncologia Milan Italy57Cogentech Cancer Genetic Test Laboratory Milan Italy

Department of Genetics and Computational Biology Queensland Institute of Medical Research Brisbane Australia

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland144Postgraduate School of Molecular Medicine Warsaw Medical University Warsaw Poland

Department of Genetics Portuguese Oncology Institute Porto Portugal

Department of Genetics Portuguese Oncology Institute Porto Portugal153Biomedical Sciences Institute University of Porto Portugal

Department of Genetics University Medical Center Groningen University Groningen The Netherlands

Department of Genetics University of Pretoria Pretoria South Africa

Department of Gynaecology and Obstetrics Division of Tumor Genetics Klinikum rechts der Isar Technical University Munich Munich Germany

Department of Gynaecology and Obstetrics University Hospital Carl Gustav Carus Technical University Dresden Dresden Germany

Department of Gynaecology and Obstetrics University Hospital Düsseldorf Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany

Department of Gynecologic Oncology Roswell Park Cancer Institute Buffalo New York

Department of Gynecology and Obstetrics University Medical Center Schleswig Holstein Campus Kiel Germany

Department of Health Research and Policy Stanford University School of Medicine Stanford California

Department of Health Sciences Research Mayo Clinic Rochester Minnesota

Department of Hematology and Oncology University of Kansas Medical Center Kansas City

Department of Human Genetics and Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

Department of Human Genetics and Department of Pathology Leiden University Medical Center Leiden The Netherlands

Department of Human Genetics Radboud University Nijmegen Medical Centre Nijmegen The Netherlands

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota159Department of Health Sciences Research Mayo Clinic Rochester Minnesota

Department of Medical Genetics University Medical Center Utrecht Utrecht The Netherlands

Department of Medical Oncology Beth Israel Deaconess Medical Center Boston Massachusetts

Department of Medical Oncology Family Cancer Clinic Erasmus University Medical Center Rotterdam The Netherlands

Department of Medical Science University of Turin and AO Città della Salute e della Scienza Turin Italy

Department of Medicine and Genetics University of California San Francisco

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Medicine University La Sapienza Rome Italy

Department of OB GYN and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Obstetrics and Gynecology University of Helsinki and Helsinki University Central Hospital Helsinki Finland

Department of Oncological Sciences Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City

Department of Oncology Lund University Lund Sweden

Department of Oncology Lund University Lund Sweden12Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Oncology Sahlgrenska University Hospital Gothenburg Sweden

Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City

Department of Pathology Landspitali University Hospital Reykjavík Iceland147BMC Faculty of Medicine University of Iceland Reykjavik Iceland

Department of Population Sciences Beckman Research Institute of City of Hope Duarte California

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles

Department of Preventive Medicine Seoul National University College of Medicine and Cancer Research Institute Seoul National University Seoul Korea

Department of Radiation Sciences Oncology Umeå University Umeå Sweden

Department of Surgery Daerim St Mary's Hospital Seoul Korea

Department of Surgery Soonchunhyang University and Hospital Seoul Korea

Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents Pomeranian Medical University Szczecin Poland

Departments of Oncology or Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Departments of Pediatrics and Medicine Columbia University New York New York

Division of Cancer Medicine Peter MacCallum Cancer Centre East Melbourne Victoria Australia 25Sir Peter MacCallum Department of Oncology University of Melbourne Melbourne Australia

Division of Cancer Prevention and Genetics Istituto Europeo di Oncologia Milan Italy

Division of Clinical Genetics Department of Clinical and Experimental Medicine Linköping University Linköping Sweden

Divison of Human Cancer Genetics Departments of Internal Medicine and Molecular Virology Immunology and Medical Genetics Comprehensive Cancer Center Ohio State University Columbus

Divison of Human Genetics Department of Internal Medicine Comprehensive Cancer Center Ohio State University Columbus

Evanston Hospital Evanston Illinois

Family Cancer Clinic Netherlands Cancer Institute Amsterdam The Netherlands

Ferguson Smith Centre for Clinical Genetics Yorkhill Hospitals Glasgow United Kingdom

Fox Chase Cancer Center Philadelphia Pennsylvania

Genetic Counseling Unit Hereditary Cancer Program IDIBELL Catalan Institute of Oncology Barcelona Spain

Genetic Counseling Unit Hereditary Cancer Program IDIBGI Catalan Institute of Oncology Girona Spain

Genetic Medicine Manchester Academic Health Sciences Centre Central Manchester University Hospitals NHS Foundation Trust Manchester United Kingdom

GOG Statistical and Data Center Buffalo New York

Hong Kong Hereditary Breast Cancer Family Registry Hong Kong135Cancer Genetics Center Hong Kong Sanatorium and Hospital Hong Kong136Department of Surgery University of Hong Kong Hong Kong

Hospital clinico Universitario Lozano Blesa Instituto de investigación sanitaria de Aragón Zaragoza Spain

Human Genetics Group and Genotyping Unit Spanish National Cancer Centre Madrid Spain

Human Genetics Group Spanish National Cancer Centre Madrid Spain

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua Italy

INSERM U1052 CNRS UMR5286 Université Lyon 1 Centre de Recherche en Cancérologie de Lyon Lyon France

Institut Curie Department of Tumour Biology Paris France

Institut Curie Department of Tumour Biology Paris France98Institut Curie INSERM U830 Paris France99Université Paris Descartes Sorbonne Paris Cité France

Institut Curie Department of Tumour Biology Paris France99Université Paris Descartes Sorbonne Paris Cité France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute of Biology and Molecular Genetics Universidad de Valladolid Valladolid Spain

Institute of Cell and Molecular Pathology Hannover Medical School Hannover Germany

Institute of Human Genetics Campus Virchov Klinikum Charite Berlin Berlin Germany

Institute of Human Genetics Department of Human Genetics University Hospital Heidelberg Heidelberg Germany

Institute of Human Genetics Technical University Dresden Dresden Germany

Institute of Human Genetics University Medical Center Schleswig Holstein Campus Kiel Germany

Institute of Human Genetics University of Regensburg Regensburg Germany

Institute of Medical Genetics Catholic University A Gemelli Hospital Rome Italy

Instituto de Genética Humana Pontificia Universidad Javeriana Bogotá Colombia65Molecular Genetics of Breast Cancer Deutsches Krebsforschungszentrum Heidelberg Germany

Laboratoire d'Oncogénétique Hôpital René Huguenin Institut Curie Saint Cloud France

Laboratoire d'Oncologie Moléculaire Humaine Centre Oscar Lambret Lille France

Latvian Biomedical Research and Study Centre Riga Latvia

Lombardi Comprehensive Cancer Center Georgetown University Washington DC

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital and University of Toronto Toronto Ontario Canada

Medical Genetics Division Centre Hospitalier Universitaire de Québec Quebec City Quebec Canada151Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua Italy

Molecular Diagnostic Unit Hereditary Cancer Program IDIBELL Catalan Institute of Oncology Barcelona Spain

Molecular Diagnostics Laboratory IRRP National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis Athens Greece

Molecular Genetics Laboratory Cruces University Hospital Barakaldo Bizkaia Spain

Molecular Genetics of Breast Cancer Deutsches Krebsforschungszentrum Heidelberg Germany

Molecular Genetics of Breast Cancer Deutsches Krebsforschungszentrum Lahore Pakistan

Molecular Oncology Laboratory Hospital Clinico San Carlos IdISSC Madrid Spain

N N Petrov Institute of Oncology St Petersburg Russia

New York University New York New York

Northern Ireland Regional Genetics Centre Belfast City Hospital Belfast United Kingdom

NorthShore University HealthSystem Department of Medicine Evanston Illinois

Ohio State Good Samaritan Hospital Cincinnati

Oncogenetics Laboratory Vall d'Hebron Institute of Oncology Universitat Autonoma de Barcelona Barcelona Spain139University Hospital of Vall d'Hebron Barcelona Spain

Oncogenetics Team Institute of Cancer Research and Royal Marsden NHS Foundation Trust London United Kingdom

Oncogénétique Clinique Hôpital René Huguenin Institut Curie Saint Cloud France

Oncology Institute Rivkah Ziv Medical Center Zefat Israel

Oncology Institute Sheba Medical Center Tel Hashomer Israel

Oncology Service Hospital de la Santa Creu i Sant Pau Barcelona Spain

Oxford Regional Genetics Service Churchill Hospital Oxford United Kingdom

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montreal Quebec Canada161Department of Medical Genetics University of Cambridge Cambridge United Kingdom

Section of Genetic Oncology Department of Oncology University of Pisa and University Hospital of Pisa Pisa Italy

Section of Molecular Diagnostics Department of Clinical Biochemistry Aalborg University Hospital Aalborg Denmark

Service de Génétique Biologique Histologie Biologie du Développement et de la Reproduction Centre Hospitalier Universitaire de Besançon Besançon France

Service de Génétique Centre Hospitalier Universitaire Bretonneau Tours France

Sheba Medical Center Tel Aviv Israel

Sheffield Clinical Genetics Service Sheffield Children's Hospital Sheffield United Kingdom

South East of Scotland Regional Genetics Service Western General Hospital Edinburgh United Kingdom

South East Thames Regional Genetics Service Guy's Hospital London United Kingdom

South West Regional Genetics Service Bristol United Kingdom

Susanne Levy Gertner Oncogenetics Unit Sheba Medical Center Tel Hashomer Israel

Tufts University Medford Massachusetts

UCLA Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Center Los Angeles California

Unit of Genetic Counselling Medical Oncology Department Istituto Nazionale Tumori Regina Elena Rome Italy

Unit of Hereditary Cancer IRCCS AOU San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genoa Italy

Unit of Medical Genetics Department of Preventive and Predictive Medicine Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Preventive and Predictive Medicine Fondazione IRCCS Istituto Nazionale Tumori Milan Italy60IFOM Fondazione Istituto FIRC di Oncologia Molecolare Milan Italy

Unité d'Oncogénétique CLCC Paul Strauss Strasbourg France

Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents Hospices Civils de Lyon Centre Léon Bérard Lyon France

Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents Hospices Civils de Lyon Centre Léon Bérard Lyon France101INSERM U1052 CNRS UMR5286 Université Lyon 1 Centre de Recherche en Cancérologie de Lyon Lyon France

Université Lyon 1 CNRS UMR5558 Lyon France103Unité de Prévention et d'Epidémiologie Génétique Centre Léon Bérard Lyon France

University of North Carolina Chapel Hill

University of Texas MD Anderson Cancer Center Houston

Vilnius University Hospital Santariskiu Clinics Hematology Oncology and Transfusion Medicine Center Department of Molecular and Regenerative Medicine State Research Institute Innovative Medicine Center Vilnius Lithuania

Wessex Clinical Genetics Service Princess Anne Hospital Southampton United Kingdom

West Midlands Regional Genetics Service Birmingham Women's Hospital Healthcare NHS Trust Edgbaston Birmingham United Kingdom

Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles California

Yale University School of Medicine New Haven Connecticut

Yorkshire Regional Genetics Service Leeds United Kingdom

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Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

Functional evaluation of variants of unknown significance in the BRCA2 gene identified in genetic testing

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3