Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.

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Journal
Nature Communications
Published
2025-05-24
DOI
https://doi.org/10.1038/s41467-025-59979-6
Citations
4
Primary Topic
BRCA gene mutations in cancer
Type
article
Field-Weighted Citation Impact
7.27

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article

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

Chunling Hu, Marjanka K. Schmidt, Marc Naven, A. Heather Eliassen et al.
4 citations
Nature Communications
BRCA gene mutations in cancer
7.27
article

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

Chunling Hu, Marjanka K. Schmidt, Marc Naven, A. Heather Eliassen, Natalia Bogdanova, Alpa V. Patel, Fergus J. Couch, Peter A. Fasching, Jingmei Li, Melissa H. Cessna, Jose E. Castelao, Jenny Chang‐Claude, Manuela Gago-Domínguez, Mihalis I. Panayiotidis, Thilo Dörk, Qin Wang, Jonine D. Figueroa, Sacha J. Howell, Kathryn J. Ruddy, Thérèse Truong, Lauren R. Teras, Jeffrey N. Weitzel, Joe Dennis, Song Yao, Kenneth Muir, Archie Campbell, Eric C. Polley, Caroline Baynes, Soo‐Hwang Teo, Ute Hamann, Clara Bodelón, Christine B. Ambrosone, Alison M. Dunning, Kristia Yiangou, Anna González‐Neira, Georgia Chenevix‐Trench, Roger Laughlin Milne, Michael T. Parsons, Muhammad Usman Rashid, Thomas U. Ahearn, Denise G O'Mahony, Kyriaki Michailidou, Peter Devilee, Craig Luccarini, Douglas F. Easton, Irene L. Andrulis, Kristen D. Brantley, Andreas Hadjisavvas, Melissa Cline, Peter Kraft, Anna Jakubowska, Gary Zirpoli, Sean V. Tavtigian, Weang-Kee Ho, Wenan Chen, Paul Livermore Auer, Maria Zanti, Emmanouil Saloustros, Susan M. Domchek, Christopher A. Haiman, Elinor J. Sawyer, Celine M. Vachon, Nadia Obi, Nicola J. Camp, Katherine L. Nathanson, Arcangela De Nicolo, Stig E. Bojesen, Arto Mannermaa, Artitaya Lophatananon, Montserrat García‐Closas, Rocío Núñez‐Torres, Felix Graßmann, Siddhartha Yadav, Veronique Kiak Mien Tan, Nicholas Boddicker, Leila Dorling, Steven N. Hart, Don Conroy, D. Gareth Evans, Paul D.P. Pharoah, Janet E. Olson, Geok Hoon Lim, Melissa C. Southey, Julie R. Palmer, Fei Chen, Marı́a Elena Martı́nez, Reiner Hoppe, Amy Trentham-Dietz, Diana Torres, Amanda B. Spurdle, Dimitriοs Mavroudis, Antonis C. Antoniou, James V. Lacey, David E. Goldgar, Yon‐Dschun Ko, Gord Glendon, Henrik Flyger, Manjeet K. Bolla, Elza K. Khusnutdinova, Kamila Czene
article en
4 citations

Abstract

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.

Nature CommunicationsVol. 16(1)
Intermountain Healthcare (US), Boston University (US), Agency for Science, Technology and Research (SG), University of Southern California (US), University of Copenhagen (DK), Oslo University Hospital (NO), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), American Cancer Society (US), Mount Sinai Hospital (CA), Roswell Park Comprehensive Cancer Center (US), National Institutes of Health (US), University of Wisconsin–Madison (US), Harvard University (US), University of Thessaly (GR), Inserm (FR), University of Nottingham Malaysia Campus (MY), Universität Hamburg (DE), The University of Melbourne (AU), National University of Singapore (SG), Chicago Department of Public Health (US), University of Eastern Finland (FI), German Cancer Research Center (DE), King's College London (GB), University of Oslo (NO), University of California, Santa Cruz (US), University of Toronto (CA), Université de Versailles Saint-Quentin-en-Yvelines (FR), Cancer Council Victoria (AU), University of Washington (US), Medical College of Wisconsin (US), Lunenfeld-Tanenbaum Research Institute (CA), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), Heidelberg University (DE), Singapore General Hospital (SG), Pontificia Universidad Javeriana (CO), University of Cambridge (GB), Manchester Academic Health Science Centre (GB), Leiden University Medical Center (NL), Huntsman Cancer Institute (US), Copenhagen University Hospital (DK), Edinburgh Cancer Research (GB), Gentofte Hospital (DK), Karolinska Institutet (SE), University of Manchester (GB), The Netherlands Cancer Institute (NL), University of Malaya (MY), Medizinische Hochschule Hannover (DE), University of California San Diego (US), University of Chicago (US), Universitätsklinikum Erlangen (DE), Fred Hutch Cancer Center (US), Spanish National Cancer Research Centre (ES), Cancer Research Malaysia (MY), Manchester University NHS Foundation Trust (GB), Kuopio University Hospital (FI), Complejo Hospitalario Universitario de Santiago (ES), SingHealth Duke-NUS Academic Medical Centre (SG), The University of Kansas Cancer Center (US), University of Wisconsin Carbone Cancer Center (US), Centre de recherche en Epidémiologie et Santé des Populations (FR), Ufa Institute of Chemistry (RU), St Mary's Hospital (GB), University Medical Center Hamburg-Eppendorf (DE), City of Hope (US), Oncode Institute (NL), KK Women's and Children's Hospital (SG), Institute of Biochemistry and Genetics of Ufa Scientific Centre (RU), Dana-Farber Cancer Institute (US), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Monash Health (AU), Fundación Pública Galega de Medicina Xenómica (ES), Mayo Clinic in Arizona (US), University Cancer Center Hamburg (DE), Riga Stradiņš University (LV), Duke-NUS Medical School (SG), Human Longevity (United States) (US), Shaukat Khanum Memorial Cancer Hospital and Research Center (PK), Cancer Research UK Manchester Institute (GB), National Cancer Centre Singapore (SG), University Hospital of Heraklion (GR), National Cancer Institute (US), Mayo Clinic in Florida (US), Johanniter-Krankenhaus Bonn (DE), Instituto de Investigación Sanitaria de Santiago (ES), Comprehensive Cancer Center Erlangen (DE), National University Health System (SG), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Servicio Gallego de Salud (ES), International Hereditary Cancer Center (PL), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Division of Cancer Epidemiology and Genetics, Cyprus Institute of Neurology and Genetics (CY), Monash University (AU), Genome Institute of Singapore (SG), University of Pennsylvania (US), Pomeranian Medical University (PL), University of Tübingen (DE), University of Edinburgh (GB), Mississippi State University (US)
U.S. Department of Health and Human Services, American Cancer Society, Susan G. Komen for the Cure, California Department of Public Health, Alexander von Humboldt-Stiftung, University of California, University of Southern California, Division of Cancer Prevention, National Cancer Institute, Itä-Suomen Yliopisto, University of Wisconsin Carbone Cancer Center, Sundhed og Sygdom, Det Frie Forskningsråd, Deutsches Krebsforschungszentrum, Genome Canada, Wellcome Trust, Huntsman Cancer Foundation, Huntsman Cancer Institute, Scottish Government, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Fondation du cancer du sein du Québec, Government of Canada, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Breast Cancer Campaign, Scottish Funding Council, Breast Cancer Research Trust, University of Cambridge, King's College London, European Commission, National Breast Cancer Foundation, Cancer Institute NSW, National Research Foundation, Agency for Science, Technology and Research, National University of Singapore, National Research Foundation Singapore, Robert Bosch Stiftung, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Research Promotion Foundation, Russian Foundation for Basic Research, Bundesministerium für Bildung und Forschung, Cancerfonden, Gentofte Hospital, Ministerie van Volksgezondheid, Welzijn en Sport, Ministerio de Economía y Competitividad, Deutsche Gesetzliche Unfallversicherung, Ministerio de Sanidad, Servicios Sociales e Igualdad, Karolinska Institutet, Kuopion Yliopistollinen Sairaala, Stockholms Läns Landsting, University of Crete, Fondation de France, Norges Forskningsråd, Medizinischen Hochschule Hannover, Deutsche Krebshilfe, Institut National Du Cancer, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, Xunta de Galicia, National University Health System, Ministry of Science and Higher Education of the Russian Federation, National Institutes of Health, Centers for Disease Control and Prevention, U.S. Army, University of California, San Francisco, Chief Scientist Office, Scottish Government Health and Social Care Directorate, Manchester Biomedical Research Centre, Center for Agroforestry, University of Missouri, Canadian Institutes of Health Research, Medical Research Council, Engineering and Physical Sciences Research Council, National Health and Medical Research Council, Cancer Council South Australia, Cancer Council Victoria, Cancer Council NSW, Cancer Council Tasmania, National Medical Research Council, Instituto de Salud Carlos III, Programme Grants for Applied Research, Servicio Gallego de Salud, NIHR Cambridge Biomedical Research Centre, National Cancer Institute, Medical Research and Materiel Command, Division of Cancer Epidemiology and Genetics, National Cancer Institute
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BRCA gene mutations in cancer
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