Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

2nd Department of Medical Oncology EUROMEDICA General Clinic of Thessaloniki Aristotle University of Thessaloniki School of Medicine Thessaloniki Greece

Biomedical Network on Rare Diseases Madrid Spain

Biomedical Sciences Institute University of Porto Porto Portugal

BMC Faculty of Medicine University of Iceland Reykjavik Iceland

Breast Cancer Research Unit Cancer Research Institute University Malaya Medical Centre Kuala Lumpur Malaysia

Cancer Research Initiatives Foundation Sime Darby Medical Centre Subang Jaya Selangor Malaysia

Cancer Research Institute Seoul National University Seoul Korea

Cancer Research Malaysia Subang Jaya Selangor Malaysia

Cancer Risk Factors and Life Style Epidemiology Unit Institute for Cancer Research Prevention and Clinical Network Florence Italy

Cancer Sciences Academic Unit Faculty of Medicine University of Southampton Southampton United Kingdom

Center for Clinical Cancer Genetics The University of Chicago Chicago Illinois

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Hereditary Breast and Ovarian Cancer University Hospital of Cologne Cologne Germany

Center for Integrated Oncology University Hospital of Cologne Cologne Germany

Center for Medical Genetics NorthShore University HealthSystem Evanston Illinois

Center for Molecular Medicine Cologne University of Cologne Cologne Germany

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge United Kingdom

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

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Centre for Medical Genetics Ghent University Ghent Belgium

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

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts

Clinical Cancer Genetics City of Hope Duarte California

Clinical Cancer Genetics Program Division of Human Genetics Department of Internal Medicine The Comprehensive Cancer Center The Ohio State University Columbus Ohio

Clinical Genetic Unit Department of Paediatrics Zealand University Hospital Roskilde Denmark

Clinical Genetics Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam the Netherlands

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland

Clinical Genetics Department St Michael's Hospital Bristol United Kingdom

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London United Kingdom

Clinical Genetics Karolinska Institutet Stockholm Sweden

Clinical Genetics Research Lab Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York New York

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York

Dana Farber Cancer Institute Boston Massachusetts

Département d'Hématologie Oncologie Médicale Centre Antoine Lacassagne Nice France

Department of Basic Sciences Shaukat Khanum Memorial Cancer Hospital and Research Centre Lahore Pakistan

Department of Biomedical Sciences Seoul National University Graduate School Seoul Korea

Department of Breast Medical Oncology and Clinical Genetics Program University of Texas MD Anderson Cancer Center Houston Texas

Department of Cancer Biology and Genetics The Ohio State University Columbus Ohio

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

Department of Chemotherapy National Institute of Oncology Budapest Hungary

Department of Clinical Genetics Aalborg University Hospital Aalborg Denmark

Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark

Department of Clinical Genetics Alder Hey Hospital Liverpool United Kingdom

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia Pennsylvania

Department of Clinical Genetics Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands

Department of Clinical Genetics Lund University Hospital Lund Sweden

Department of Clinical Genetics Maastricht University Medical Center Maastricht the Netherlands

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Genetics Rigshospitalet Copenhagen Denmark

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

Department of Clinical Genetics South Glasgow University Hospitals Glasgow United Kingdom

Department of Clinical Genetics Vejle Hospital Vejle Denmark

Department of Clinical Genetics VU University Medical Center Amsterdam the Netherlands

Department of Clinical Pathology The University of Melbourne Melbourne Victoria Australia

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

Department of Epidemiology The Netherlands Cancer Institute Amsterdam the Netherlands

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

Department of Genetics Portuguese Oncology Institute Porto Portugal

Department of Gynaecology and Obstetrics University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Kiel Germany

Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany

Department of Gynecology and Obstetrics Ludwig Maximilian University of Munich Munich Germany

Department of Gynecology and Obstetrics Technical University of Dresden Dresden Germany

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

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Internal Medicine Division of Oncology University of Kansas Medical Center Westwood Kansas

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Department of Medical and Biological Sciences University of Udine Udine Italy

Department of Medical Genetics University Medical Center Utrecht the Netherlands

Department of Medical Genetics University of Cambridge Cambridge United Kingdom

Department of Medical Oncology Beth Israel Deaconess Medical Center Boston Massachusetts

Department of Medical Oncology Family Cancer Clinic Erasmus MC Cancer Institute Rotterdam the Netherlands

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

Department of Medicine Huntsman Cancer Institute Salt Lake City Utah

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Molecular Medicine University La Sapienza Rome Italy

Department of OB GYN Medical University of Vienna Vienna Austria

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

Department of Oncology and Haematology University of Modena and Reggio Emilia Modena Italy

Department of Oncology Hospital Clinico San Carlos IdISSC Madrid Spain

Department of Oncology Karolinska Institutet Stockholm Sweden

Department of Oncology Landspitali University Hospital Reykjavik Iceland

Department of Oncology Lund University and Skåne University Hospital Lund Sweden

Department of Oncology Mayo Clinic Rochester Minnesota

Department of Oncology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

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

Department of Pathology Hong Kong Sanatorium and Hospital Happy Valley Hong Kong

Department of Pathology Landspitali University Hospital 101 Reykjavik Iceland

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

Department of Preventive Medicine Gacheon University College of Medicine Incheon Republic of Korea

Department of Preventive Medicine Seoul National University College of Medicine Seoul Korea

Department of Radiation Oncology Dana Farber Cancer Institute and Brigham and Women's Hospital Boston Massachusetts

Department of Surgery Daerim Saint Mary's Hospital Seoul Korea

Department of Surgery Hong Kong Sanatorium and Hospital Happy Valley Hong Kong

Department of Surgery Seoul National University Bundang Hospital Seongnam Korea

Department of Surgery Soonchunhyang University Bucheon Hospital Bucheon Korea

Department of Surgery Soonchunhyang University College of Medicine and Soonchunhyang University Hospital Seoul Korea

Department of Surgery The University of Hong Kong Pok Fu Lam Hong Kong

Department of Surgery Ulsan University College of Medicine and Asan Medical Center Seoul Korea

Department of Tumour Biology INSERM U830 Paris France

Department of Urology Medical University of Vienna Vienna Austria

Department of Women's Health Tubingen University Hospital Tubingen Germany

Departments of Pediatrics and Medicine Columbia University New York New York

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

Division of Cancer Prevention and Genetics IEO European Institute of Oncology IRCCS Milan Italy

Division of Evolution and Genomic Medicine School of Biological Sciences Faculty of Biology Medicine and Health and Manchester Academic Health Science Centre University of Manchester Manchester United Kingdom

Division of Functional Onco genomics and Genetics Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

Division of Gynaecology and Obstetrics Klinikum rechts der Isar der Technischen Universität München Munich Germany

Division of Oncology Department of Medicine Stanford Cancer Institute Stanford University School of Medicine Stanford California

Family Cancer Clinic The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Fred A Litwin Center for Cancer Genetics Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

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

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

Genetic Epidemiology of Cancer Team Inserm U900 Paris France

Genome Diagnostics Program IFOM the FIRC Institute of Molecular Oncology Milan Italy

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Centre Québec City Québec Canada

Harvard T H Chan School of Public Health Boston Massachusetts

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

High Risk and Cancer Prevention Group Vall d'Hebron Institute of Oncology University Hospital Vall d'Hebron Barcelona Spain

Hong Kong Hereditary Breast Cancer Family Registry Cancer Genetics Centre Happy Valley Hong Kong

Human Cancer Genetics Programme Spanish National Cancer Research Centre Madrid Spain

Human Genetics Group Spanish National Cancer Research Centre Madrid Spain

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

INBIOMED Faculty of Medicine CONICET and CEMIC Department of Clinical Chemistry Medical Direction University of Buenos Aires Buenos Aires Argentina

Institut Curie Paris France

Institute for Medical Genetics and Human Genetics Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

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

Institute of Cancer and Genomic Sciences University of Birmingham Birmingham United Kingdom

Institute of Cell and Molecular Pathology Hannover Medical School Hannover Germany

Institute of Human Genetics Hannover Medical School Hannover Germany

Institute of Human Genetics Pontificia Universidad Javeriana Bogota Colombia

Institute of Human Genetics University Hospital Heidelberg Heidelberg Germany

Institute of Human Genetics University Hospital Leipzig Leipzig Germany

Institute of Human Genetics University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Kiel Germany

Institute of Human Genetics University of Münster Münster Germany

Institute of Medical Genetics and Applied Genomics University of Tübingen Tübingen Germany

Istituto Nazionale Tumori 'Giovanni Paolo 2 Bari Italy

Laboratory Medicine Program University Health Network Toronto Ontario Canada

Latvian Biomedical Research and Study Centre Riga Latvia

LIFE Leipzig Research Centre for Civilization Diseases University of Leipzig Leipzig Germany

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh Pennsylvania

Manchester Centre for Genomic Medicine St Mary's Hospital Central Manchester University Hospitals NHS Foundation Trust and Manchester Academic Health Science Centre Manchester United Kingdom

Medical Genetics Unit St George's University of London London United Kingdom

Medical Oncology Department Hospital Clínico San Carlos Instituto de Investigación Sanitaria San Carlos Madrid Spain

Mines ParisTech Fontainebleau France

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

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research Demokritos Athens Greece

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

North East Thames Regional Genetics Service Great Ormond Street Hospital for Children NHS Trust London United Kingdom

North West Thames Regional Genetics Service Kennedy Galton Centre The North West London Hospitals NHS Trust Middlesex United Kingdom

Oncogenetics Group Clinical and Molecular Genetics Area Vall d'Hebron Institute of Oncology University Hospital Barcelona Spain

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

Parkville Familial Cancer Centre Peter MacCallum Cancer Center Melbourne Victoria Australia

Peter MacCallum Cancer Center Melbourne Victoria Australia

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal Quebec Canada

School of Medicine University of Iceland Reykjavik Iceland

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

Section of Molecular Diagnostics Clinical Biochemistry Aalborg University Hospital Aalborg Denmark

Section of Molecular Genetics Department of Laboratory Medicine University Hospital of Pisa Pisa Italy

Service de Biologie de la Reproduction Cytogénétique et Génétique Médicale CHI Poissy Saint Germain Poissy France

Service de Génétique Institut Curie Paris France

Service Régional Oncogénétique Poitou Charentes CH Niort Niort France

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

Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne Victoria Australia

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

The Hereditary Breast and Ovarian Cancer Research Group Netherlands Coordinating center The Netherlands Cancer Institute Amsterdam the Netherlands

The University of Chicago Pritzker School of Medicine Chicago Illinois

Translational Research Laboratory IDIBELL Catalan Institute of Oncology CIBERONC Barcelona Spain

ULSS 3 Serenissima U O C Oncologia ed Ematologia Oncologica Mirano Venice Italy

Unit of Hereditary Cancer Department of Epidemiology Prevention and Special Functions IRCCS AOU San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genoa Italy

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research in Fondazione IRCCS Milan Italy

Unité d'oncogénétique Centre de Lutte Contre le Cancer Centre Georges François Leclerc Dijon France

Unité d'Oncogénétique Centre de Lutte Contre le Cancer Paul Strauss Strasbourg France

Unité de Prévention et d'Epidémiologie Génétique Centre Léon Bérard Lyon France

Université Paris Descartes Paris France

UO Anatomia Patologica Ospedale di Circolo Università dell'Insubria Varese Italy

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

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds United Kingdom

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J Urol. 2020 Sep;204(3):619-620. doi: 10.1097/JU.0000000000001176.01. PubMed

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