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

Zanti, M.
; 
O'Mahony, D. G.
; 
Parsons, M. T.
; 
Dorling, L.
; 
Dennis, J.
; 
Boddicker, N. J.
; 
Chen, W.
; 
Hu, C.
; 
Naven, M.
; 
Yiangou, K.
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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.
Authors
Zanti, M.
O'Mahony, D. G.
Parsons, M. T.
Dorling, L.
Dennis, J.
Boddicker, N. J.
Chen, W.
Hu, C.
Naven, M.
Yiangou, K.
Ahearn, T. U.
Ambrosone, C. B.
Andrulis, I. L.
Antoniou, A. C.
Auer, P. L.
Baynes, C.
Bodelon, C.
Bogdanova, N. V.
Bojesen, S. E.
Bolla, M. K.
Brantley, K. D.
Camp, N. J.
Campbell, A.
Castelao, J. E.
Cessna, M. H.
Chang-Claude, J.
Chen, F.
Chenevix-Trench, G.
Conroy, D. M.
Czene, K.
De Nicolo, A.
Domchek, S. M.
Dörk, T.
Dunning, A. M.
Eliassen, A. H.
Evans, D. G.
Fasching, P. A.
Figueroa, J. D.
Flyger, H.
Gago-Dominguez, M.
García-Closas, M.
Glendon, G.
González-Neira, A.
Grassmann, F.
Hadjisavvas, A.
Haiman, C. A.
Hamann, U.
Hart, S. N.
Hartman, M. B. A.
Ho, W. K.
Hodge, J. M.
Hoppe, R.
Howell, S. J.
Jakubowska, A.
Khusnutdinova, E. K.
Ko, Y. D.
Kraft, P.
Kristensen, V. N.
Lacey, J. V.
Li, J.
Lim, G. H.
Lindström, S.
Lophatananon, A.
Luccarini, C.
Mannermaa, A.
Martinez, M. E.
Mavroudis, D.
Milne, R. L.
Muir, K.
Nathanson, K. L.
Nuñez-Torres, R.
Obi, N.
Olson, J. E.
Palmer, J. R.
Panayiotidis, M. I.
Patel, A. V.
Pharoah, P. D. P.
Polley, E. C.
Rashid, M. U.
Ruddy, K. J.
Saloustros, E.
Sawyer, E. J.
Schmidt, M. K.
Southey, M. C.
Tan, V. K.
Teo, S. H.
Teras, L. R.
Torres, D.
Trentham-Dietz, A.
Truong, T.
Vachon, C. M.
Wang, Q.
Weitzel, J. N.
Yadav, S.
Yao, S.
Zirpoli, G. R.
Cline, M. S.
Devilee, P.
Tavtigian, S. V.
Goldgar, D. E.
Couch, F. J.
Easton, D. F.
Spurdle, A. B.
Michailidou, K.
Affiliation
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Institute, Buffalo, NY, USA. Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Division of Biostatistics, Data Science Institute and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. Department of Population Science, American Cancer Society, Atlanta, GA, USA. Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, UK. Oncology and Genetics Unit, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation, Complejo Hospitalario Universitario de Santiago, SERGAS, Vigo, Spain. Department of Pathology and Intermountatin Biorepository, Intermountain Health, Salt Lake City, UT, USA. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy. Institute of Oncology and Molecular Genetics, Rīga Stradiņš University, Riga, Latvia. Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany. Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK. Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK. Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain. Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany. Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore City, Singapore. Department of Surgery, National University Health System, Singapore City, Singapore. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore. Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia. School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Selangor, Malaysia. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. University of Tübingen, Tübingen, Germany. Division of Cancer Sciences, University of Manchester, Manchester, UK. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia. Ufa University of Science and Technology, Department of genetics and fundamental medicine, 450076, Ufa, Russia. Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA. City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA. Human Genetics Division, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore. Breast Department, KK Women's and Children's Hospital, Singapore City, Singapore. Duke-NUS Medical School, Singapore City, Singapore. Department of Epidemiology, University of Washington, Seattle, WA, USA. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA. Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute for Occupational and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA. Slone Epidemiology Center, Boston University, Boston, MA, USA. School of Medicine, Boston University, Boston, MA, USA. Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS, 39762, USA. Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, USA. Department of Public Health Sciences, University of Chicago, Chicago, IL, USA. Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan. Department of Oncology, Mayo Clinic, Rochester, MN, USA. Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece. School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands. Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia. Department of Breast Surgery, Singapore General Hospital, Singapore City, Singapore. Division of Surgery and Surgical Oncology, National Cancer Centre, Singapore City, Singapore. SingHealth Duke-NUS Breast Centre, Singapore City, Singapore. Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia. Department of Surgery, Faculty of Medicine, University of Malaya, UM Cancer Research Institute, Kuala Lumpur, Malaysia. Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia. Carbone Cancer Center and Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France. University of Kansas Cancer Center, Kansas City, KS, USA. UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA. Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. kyriakimi@cing.ac.cy.
Description
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2025
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All Paterson Institute for Cancer Research
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Zanti M, O'Mahony DG, Parsons MT, Dorling L, Dennis J, Boddicker NJ, et al. Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. Nature communications. 2025 May 25;16(1):4852. PubMed PMID: 40413188. Pubmed Central PMCID: PMC12103537 relevant to this work as stated below. VK-MT and GDE have received consultancies from AstraZeneca and Everything Genetic Ltd. ACA and DFE are named creators of the BOADICEA model, which has been licensed by Cambridge Enterprise (University of Cambridge). SJH has received speaker fees from AstraZeneca and Pfizer Ltd. SY has received research funding from AstraZeneca and Repare Therapeutics and participates in the advisory board for AstraZeneca. JWW has received consulting fees from Natera, MyOme, Cancer IQ, equity from Natera, and speaker fees from AstraZeneca. All the other authors declare no competing interests. Epub 2025/05/25 20:35. eng.
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https://christie.openrepository.com/handle/10541/627507
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