IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. CONCLUSIONS AND RELEVANCE: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

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

Area of Clinical and Molecular Genetics University Hospital of Vall d'Hebron Barcelona Spain

Biomedical Sciences Institute University of Porto Porto Portugal

BMC Faculty of Medicine University of Iceland Reykjavik Iceland

Breast Cancer Research Center Genetics Department Motamed Cancer Institute ACECR Tehran Iran

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

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Genetics Service National Cancer Centre Singapore Singapore

Cancer Research Institute Seoul National University Seoul Korea

Cancer Research Malaysia Subang Jaya Selangor Malaysia

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 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 Cancer Research University of Sydney at The Westmead Institute for Medical Research and Familial Cancer Service Westmead Hospital New South Wales Australia

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 Gent Belgium

Centro de Investigación en Red de Enfermedades Raras Spain

Clinical Cancer Genetics City of Hope Duarte California

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

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

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

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

Dana Farber Cancer Institute Boston Massachusetts

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 Cancer Biology and Genetics The Ohio State University Columbus

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

Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark

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

Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Genetics Rigshospitalet Copenhagen Denmark

Department of Clinical Genetics Vejle Hospital Vejle Denmark

Department of Clinical Pathology The University of Melbourne Melbourne Victoria Australia

Department of Epidemiology and Population Health Division of Oncology Department of Medicine Stanford Cancer Institute Stanford University School of Medicine Stanford California

Department of Epidemiology Mailman School of Public Health Columbia University New York New York

Department of Experimental and Clinical Biomedical Sciences University of Florence Florence Italy

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

Department of Genetics Portuguese Oncology Institute Porto Portugal

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 Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge United Kingdom

Department of Medical Oncology Beth Israel Deaconess Medical Center Boston Massachusetts

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of Molecular Medicine Sapienza University of Rome 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 Lund University Skåne University Hospital Lund Sweden

Department of Oncology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

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

Department of Pathology Landspitali University Hospital Reykjavik Iceland

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

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

Department of Surgery and Cancer Genetics Center Hong Kong Sanatorium and Hospital Happy Valley Hong Kong

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

Department of Tumour Biology INSERM U830 Paris France

Departments of Pediatrics and Medicine Columbia University New York New York

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

Division of Functional onco genomics and genetics Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

Family Cancer Clinic Netherlands Cancer Institute Amsterdam the Netherlands

Fundación Pública Galega Medicina Xenómica SERGAS Santiago de Compostela Spain

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

Genetic Epidemiology of Cancer Team Inserm U900 Paris France

Genomic Medicine Manchester Academic Health Sciences Centre Division of Evolution and Genomic Science Manchester University Manchester University Hospitals NHS Foundation Trust Manchester United Kingdom

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

Hereditary Cancer Genetics Group Vall d'Hebron Institute of Oncology Barcelona Spain

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

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

Human Genetics Group Human Cancer Genetics Programme Spanish National Cancer Research Centre Madrid Spain

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

Huntsman Cancer Institute Department of Internal Medicine University of Utah Health Salt Lake City

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

INBIOMED Faculty of Medicine UBA CONICET and Genotyping Laboratory Department of Clinical Chemistry Centro de Educacion Medica e Investigaciones Clinicas CABA Argentina

Institut Curie Paris France

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

Instituto de Investigación Sanitaria de Santiago de Compostela Santiago de Compostela Spain

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

Laboratory Medicine Program University Health Network Toronto Ontario Canada

Latvian Biomedical Research and Study Centre Riga Latvia

Lee Kong Chian School of Medicine Nanyang Technological University Singapore

Lombardi Comprehensive Cancer Center Georgetown University Washington DC

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

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh Pennsylvania

Male High Risk Clinic Uro Oncology Service Urology Department Chaim Sheba Medical Center Tel Hashomer Israel

Medical Oncology Center National Institute of Oncology Budapest Hungary

Mines ParisTech Fontainebleau France

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

Molecular Diagnostics Department of Clinical Medicine Aalborg University Hospital Aalborg University Aalborg Denmark

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

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

Parkville Familial Cancer Centre Peter MacCallum Cancer Centre Melbourne Victoria Australia

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

ProCURE Catalan Institute of Oncology IDIBELL Barcelona Spain

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

Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel

School of Medicine University of Iceland Reykjavik Iceland

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

Service de Génétique Institut Curie Paris France

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

Spanish Network on Rare Diseases Madrid Spain

The Suzanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center Ramat Gan Israel

The University of Chicago Pritzker School of Medicine Chicago Illinois

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

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Université de Paris Paris France

UO Oncologia Medica Azienda Ospedaliero Universitaria Pisana Pisa Italy

Erratum v

JAMA Oncol. 2020 Nov 1;6(11):1815. doi: 10.1001/jamaoncol.2020.4696. PubMed

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Cancer Spectrum, Family History of Cancer and Overall Survival in Men with Germline BRCA1 or BRCA2 Mutations