Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.
About this Publication
Title
Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.
Pubmed ID
39281752
(View this publication on the PubMed website)
Digital Object Identifier
Publication
medRxiv. 2024 Sep 4
Authors
Zanti M, O'Mahony DG, Parsons MT, Dorling L, Dennis J, Boddicker NJ, Chen W, Hu C, Naven M, Yiangou K, Ahearn TU, Ambrosone CB, Andrulis IL, Antoniou AC, Auer PL, Baynes C, Bodelon C, Bogdanova NV, Bojesen SE, Bolla MK, ...show more Brantley KD, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chen F, Chenevix-Trench G, NBCS Collaborators, Conroy DM, Czene K, De Nicolo A, Domchek SM, Dörk T, Dunning AM, Eliassen AH, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Glendon G, González-Neira A, Grassmann F, Hadjisavvas A, Haiman CA, Hamann U, Hart SN, Hartman MBA, Ho WK, Hodge JM, Hoppe R, Howell SJ, kConFab Investigators, Jakubowska A, Khusnutdinova EK, Ko YD, Kraft P, Kristensen VN, Lacey JV, Li J, Lim GH, Lindström S, Lophatananon A, Luccarini C, Mannermaa A, Martinez ME, Mavroudis D, Milne RL, Muir K, Nathanson KL, Nuñez-Torres R, Obi N, Olson JE, Palmer JR, Panayiotidis MI, Patel AV, Pharoah PDP, Polley EC, Rashid MU, Ruddy KJ, Saloustros E, Sawyer EJ, Schmidt MK, Southey MC, Tan VK, Teo SH, Teras LR, Torres D, Trentham-Dietz A, Truong T, Vachon CM, Wang Q, Weitzel JN, Yadav S, Yao S, Zirpoli GR, Cline MS, Devilee P, Tavtigian SV, Goldgar DE, Couch FJ, Easton DF, Spurdle AB, Michailidou K
Affiliations
- Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
- Public 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.
- 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 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.
- 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.
- 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.
- 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.
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
- 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, 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.
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
- Division of Cancer Sciences, University of Manchester, Manchester, UK.
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, 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 Computational and Quantitative Medicine, 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.
- Department of Epidemiology, University of Washington, 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.
- Moores Cancer Center, 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.
- Institute for Medical Biometry and Epidemiology, 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.
- 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 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.
- Duke-NUS Medical School, Singapore City, Singapore.
- Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
- 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 Oncological Services, University of Utah School of Medicine, Salt Lake City, UT, USA.
- Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
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, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected 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 observed 11,227 BRCA1 and BRCA2 variants, with 6,921 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 LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.
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