BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Adult Cancer Program Lowy Cancer Research Centre University of New South Wales Sydney Sydney NSW 2052 Australia

Basser Center for BRCA Abramson Cancer Center University of Pennsylvania Philadelphia PA 19066 USA

Biosciences Laboratory IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy

Biostatistics Unit The Cyprus Institute of Neurology and Genetics Nicosia 2371 Cyprus

BMC Faculty of Medicine University of Iceland Reykjavik 101 Iceland

Cancer Epidemiology Division Cancer Council Victoria Melbourne VIC 3004 Australia

Cancer Genetics and Prevention Program University of California San Francisco San Francisco CA 94143 1714 USA

Cancer Research UK Cambridge Institute University of Cambridge Cambridge CB2 0RE UK

Center for Familial Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne University of Cologne Cologne 50937 Germany

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen DK 2100 Denmark

Center for Integrated Oncology Faculty of Medicine and University Hospital Cologne University of Cologne Cologne 50937 Germany

Center for Medical Genetics NorthShore University HealthSystem Evanston IL 60201 USA

Center for Molecular Medicine Cologne Faculty of Medicine and University Hospital Cologne University of Cologne Cologne 50931 Germany

Centre for Biomedical Network Research on Rare Diseases Instituto de Salud Carlos 3 Madrid 28029 Spain

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge CB1 8RN UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge CB1 8RN UK

Centre for Cancer Research The Westmead Institute for Medical Research Sydney Australia

Centre for Medical Genetics Ghent University Gent 9000 Belgium

Centro de Investigación en Red de Enfermedades Raras Madrid 28029 Spain

Clinical Cancer Research Center Aalborg University Hospital Aalborg 9000 Denmark

Clinical Genetics Karolinska Institutet Stockholm 171 76 Sweden

Clinical Genetics Research Lab Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Computational Oncology Group Structural Biology Programme Spanish National Cancer Research Centre Madrid 28029 Spain

David Geffen School of Medicine Department of Obstetrics and Gynecology University of California at Los Angeles Los Angeles CA 90095 USA

Department of Biomedical Data Science Stanford University School of Medicine Stanford CA 94305 USA

Department of Cancer Biology and Genetics The Ohio State University Columbus OH 43210 USA

Department of Cancer Genetics Therapeutics and Ultrastructural Pathology The Cyprus Institute of Neurology and Genetics Nicosia 2371 Cyprus

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia PA 19111 USA

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen DK 2100 Denmark

Department of Clinical Medicine Aalborg University Aalborg 9000 Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 2200 Denmark

Department of Clinical Oncology A C Camargo Cancer Center São Paulo 1509900 Brazil

Department of Clinical Pathology The University of Melbourne Melbourne VIC 3010 Australia

Department of Dermatology Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City UT 84112 USA

Department of Epidemiology and Population Health Stanford University School of Medicine Stanford CA 94305 USA

Department of Experimental and Clinical Biomedical Sciences 'Mario Serio' Medical Genetics Unit University of Florence Florence 27571 Italy

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane QLD 4006 Australia

Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY 10029 USA

Department of Genetics and Pathology International Hereditary Cancer Center Pomeranian Medical University Szczecin 171 252 Poland

Department of Gynaecological Oncology Westmead Hospital Sydney NSW 2145 Australia

Department of Gynecology and Obstetrics Ribeirao Preto Medical School University of Sao Paulo Ribeirao Preto 14049 900 Brazil

Department of Internal Medicine Division of Medical Oncology University of Kansas Medical Center Westwood KS 66205 USA

Department of Laboratory Genetics Portuguese Oncology Institute of Porto Comprehensive Cancer Center Porto 4200 072 Portugal

Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge CB2 0QQ UK

Department of Medicine Division of Oncology Stanford Cancer Institute Stanford University School of Medicine Stanford CA 94304 USA

Department of Molecular Genetics University of Toronto Toronto ON M5S 1A8 Canada

Department of OB GYN and Comprehensive Cancer Center Medical University of Vienna Vienna 1090 Austria

Department of Obstetrics and Gynecology Helsinki University Hospital University of Helsinki Helsinki 00290 Finland

Department of Obstetrics and Gynecology Oregon Health and Science University Portland OR 97239 USA

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague 12000 Czech Republic

Department of Oncology Lund University and Skåne University Hospital Lund 222 41 Sweden

Department of Pathology and Laboratory Medicine The University of Kansas Medical Center Kansas City KS 66160 USA

Department of Pathology and Molecular Medicine Juravinski Hospital and Cancer Centre McMaster University Hamilton ON L8V 1C3 Canada

Department of Pathology Landspitali University Hospital Reykjavik 101 Iceland

Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai New York NY 10029 USA

Department of Population Sciences Beckman Research Institute of City of Hope Duarte CA 91010 USA

Department of Radiation Oncology Dana Farber Cancer Institute Boston MA 2215 USA

Departments of Pediatrics and Medicine Columbia University New York NY 10032 USA

Faculty of Medicine Institute of Biomedical Sciences Department of Human and Medical Genetics Vilnius University Vilnius LT 03101 Lithuania

Fred A Litwin Center for Cancer Genetics Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto ON M5G 1×5 Canada

Fundación Pública Galega de Medicina Xenómica Santiago de Compostela 15706 Spain

Genetics Service Fundación Jiménez Díaz Madrid 28040 Spain

Genome Diagnostics Program IFOM ETS the AIRC Institute of Molecular Oncology Milan 20139 Italy

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center Québec City QC G1V 4G2 Canada

Gynaecology Research Unit Hannover Medical School Hannover 30625 Germany

Hereditary Cancer Program ONCOBELL IDIBELL IGTP Catalan Institute of Oncology CIBERONC Barcelona 08908 Spain

Human Genetics Group Spanish National Cancer Research Centre Madrid 28029 Spain

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua 35128 Italy

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin 171 252 Poland

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig 04107 Germany

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague 12000 Czech Republic

Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela 15706 Spain

Knight Cancer Institute Oregon Health and Science University Portland OR 97239 USA

Latvian Biomedical Research and Study Centre Riga LV 1067 Latvia

LIFE Leipzig Research Centre for Civilization Diseases University of Leipzig Leipzig 04103 Germany

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh PA 15213 USA

Molecular Diagnostics Aalborg University Hospital Aalborg 9000 Denmark

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research 'Demokritos' Athens 15310 Greece

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg 69120 Germany

Molecular Oncology Laboratory CIBERONC Hospital Clinico San Carlos IdISSC Madrid 28040 Spain

N N Petrov Institute of Oncology St Petersburg 197758 Russia

Oncology Center Hospital Sirio Libanes São Paulo 01308 050 Brazil

Peter MacCallum Cancer Centre Melbourne VIC 3000 Australia

Population Health Program QIMR Berghofer Medical Research Institute Brisbane QLD 4006 Australia

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VIC 3168 Australia

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal QC H4A 3J1 Canada

Romagna Cancer Registry IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola 47014 Italy

School of Clinical Medicine University of New South Wales Medicine and Health University of New South Wales Sydney Sydney NSW 2052 Australia

School of Medicine and Biomedical Sciences Institute University of Porto Porto 4050 013 Portugal

Service de Génétique Institut Curie Paris 75005 France

Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne VIC 3000 Australia

SOD Genetica Molecolare University Hospital Pisa 56126 Italy

State Research Institute Centre for Innovative Medicine Vilnius 8410 Lithuania

The Daffodil Centre The University of Sydney a joint venture with Cancer Council NSW Sydney NSW Australia

The University of Chicago Pritzker School of Medicine Chicago IL 60637 USA

The University of Kansas Cancer Center Kansas City MO 66160 USA

The University of Sydney Sydney NSW 2145 Australia

Unit of Hereditary Cancer IRCCS Ospedale Policlinico San Martino Genoa 16132 Italy

Unit of Pathology IRCCS Ospedale Policlinico San Martino Genoa 16132 Italy

Unit of Preventive Medicine Molecular Bases of Genetic Risk Department of Experimental Oncology Fondazione IRCCS Istituto Nazionale dei Tumori Milan 20133 Italy

Waukesha Memorial Hospital Pro Health Care Waukesha WI 53188 USA

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Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk