Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

Academic Unit of Pathology Department of Neuroscience University of Sheffield Sheffield United Kingdom

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

Cancer and Environment Group Center for Research in Epidemiology and Population Health INSERM University Paris Sud University Paris Saclay Villejuif France

Cancer Center of Eastern Finland University of Eastern Finland Kuopio Finland

Cancer Control and Population Sciences University of Utah Salt Lake City Utah

Cancer Epidemiology Centre Cancer Council Victoria Melbourne Australia

Cancer Epidemiology Program H Lee Moffitt Cancer Center and Research Institute Tampa Florida

Cancer Research Initiatives Foundation Subang Jaya Selangor Malaysia

Cancer Research Institute Seoul National University Seoul Korea

Center for Medical Genetics Ghent University Hospita Ghent Belgium

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

Centro de Investigación en Red de Enfermedades Raras Valencia Spain

Copenhagen General Population Study Herlevand Gentofte Hospital Copenhagen University Hospital Herlev Denmark

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

Department of Biomedical Sciences Seoul National University College of Medicine Seoul Korea

Department of Breast Surgery Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

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

Department of Cancer Genetics Institute for Cancer Research Oslo University Hospital Radiumhospitalet Oslo Norway

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

Department of Clinical Genetics Erasmus University Medical Center Rotterdam the Netherlands

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 Electron Microscopy Molecular Pathology The Cyprus Institute of Neurology and Genetics Nicosia Cyprus

Department of Epidemiology Nagoya University Graduate School of Medicine Nagoya Japan

Department of Epidemiology University of California Irvine Irvine California

Department of General Medical Oncology Leuven Cancer Institute University Hospitals Leuven Leuven Belgium

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

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics University of Groningen Groningen the Netherlands

Department of Gynaecology and Obstetrics University Hospital Erlangen Friedrich Alexander University Erlangen Nuremberg Comprehensive Cancer Center Erlangen EMN Erlangen Germany

Department of Health Sciences Research Mayo Clinic Rochester Minnesota

Department of Human Genetics Leiden University Medical Center Leiden the Netherlands

Department of Human Genetics University of Chicago Chicago Illinois

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

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

Department of Medicine Division of Hematology and Oncology David Geffen School of Medicine University of California at Los Angeles Los Angeles California

Department of Molecular Genetics University of Toronto Toronto Canada

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Non Communicable Disease Epidemiology London School of Hygiene and Tropical Medicine London United Kingdom

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

Department of Obstetrics and Gynecology University of Heidelberg Heidelberg Germany

Department of Oncologic Science University of South Florida Tampa Florida

Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Department of Oncology University of Cambridge Cambridge United Kingdom

Department of Pathology The University of Melbourne Melbourne Australia

Department of Pathology University of Otago Christchurch New Zealand

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 California

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

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Radiation Oncology Hannover Medical School Hannover Germany

Department of Surgery National Taiwan University Hospital Taipei Taiwan

Department of Surgery National University Health System Singapore Singapore

Division of Breast Cancer Research The Institute of Cancer Research London United Kingdom

Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville Maryland

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan

Division of Epidemiology Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville Tennessee

Division of Genetics and Epidemiology The Institute of Cancer Research London United Kingdom

Division of Health Sciences Warwick Medical School Warwick University Coventry United Kingdom

Division of Molecular Medicine Aichi Cancer Center Research Institute Nagoya Japan

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Dr Margarete Fischer Bosch Institute of Clinical Pharmacology Stuttgart Germany

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Genotoxic Stress and Cancer Institut Curie Orsay France

German Cancer Consortium Heidelberg Germany

Gynaecology Research Unit Hannover Medical School Hannover Germany

Human Cancer Genetics Program Spanish National Cancer Research Centre Madrid Spain

Huntsman Cancer Institute and Department of Dermatology University of Utah Salt Lake City Utah

IFOM The FIRC Institute of Molecular Oncology Milan Italy

Imaging Center Department of Clinical Pathology Kuopio University Hospital Kuopio Finland

Institute for Prevention and Occupational Medicine of the German Social Accident Insurance Institute of the Ruhr University Bochum Bochum Germany

Institute of Clinical Medicine Pathology and Forensic Medicine University of Eastern Finland Kuopio Finland

Institute of Human Genetics Pontificia Universidad Javeriana Bogota Colombia

Institute of Population Health University of Manchester Manchester United Kingdom

International Agency for Research on Cancer Lyon France

K G Jebsen Center for Breast Cancer Research Institute of Clinical Medicine Faculty of Medicine University of Oslo Oslo Norway

Laboratory for Translational Genetics Department of Oncology University of Leuven Leuven Belgium

Laboratory of Cancer Genetics and Tumor Biology Cancer and Translational Medicine Research Unit Biocenter Oulu University of Oulu Oulu Finland

Laboratory of Cancer Genetics and Tumor Biology Northern Finland Laboratory Centre Oulu Oulu Finland

Laboratory of Experimental Oncology Department of Oncology University Hospitals Leuven Leuven Belgium

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Canada

Molecular Diagnostics Laboratory Institute of Radioisotopes and Radiodiagnostic Products Athens Greece

Molecular Epidemiology Group German Cancer Research Center Heidelberg Germany

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

National Cancer Institute Bangkok Thailand

National Center for Tumor Diseases University of Heidelberg Heidelberg Germany

Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Research Center Institute Curie Orsay France

Research Oncology Guy's Hospital King's College London London United Kingdom

Saw Swee Hock School of Public Health National University of Singapore Singapore Singapore

School of Public Health China Medical University Taichung Taiwan

Shanghai Municipal Center for Disease Control and Prevention Shanghai China

Sheffield Cancer Research Department of Oncology and Metabolism University of Sheffield Sheffield United Kingdom

Singapore Eye Research Institute National University of Singapore Singapore Singapore

Taiwan Biobank Institute of Biomedical Sciences Academia Sinica Taipei Taiwan

Unit of Hereditary Cancers IRCCS AOU San Martino Genova Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Preventive and Predictive Medicine Fondazione IRCCS Milan Italy

University Cancer Center Hamburg University Medical Center Hamburg Eppendorf Hamburg Germany

University of Hawaii Cancer Center Honolulu Hawaii

University of Tübingen Tübingen Germany

Usher Institute of Population Health Sciences and Informatics The University of Edinburgh Medical School Edinburgh United Kingdom

Vesalius Research Center Leuven Belgium

Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford United Kingdom

Westmead Millenium Institute for Medical Research University of Sydney Sydney Australia

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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

BRCA1 and BRCA2 5' noncoding region variants identified in breast cancer patients alter promoter activity and protein binding