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Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.
Nat Commun. 2025 May 25; 16(1):4852.NC

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.

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Authors+Show Affiliations

Zanti M
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
O'Mahony DG
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Parsons MT
Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Dorling L
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Dennis J
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Boddicker NJ
Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
Chen W
Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
Hu C
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Naven M
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Yiangou K
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Ahearn TU
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Ambrosone CB
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Institute, Buffalo, NY, USA.
Andrulis IL
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.
Antoniou AC
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Auer PL
Division of Biostatistics, Data Science Institute and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Baynes C
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Bodelon C
Department of Population Science, American Cancer Society, Atlanta, GA, USA.
Bogdanova NV
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
Bojesen SE
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.
Bolla MK
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Brantley KD
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Camp NJ
Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Campbell A
Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, UK.
Castelao JE
Oncology and Genetics Unit, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation, Complejo Hospitalario Universitario de Santiago, SERGAS, Vigo, Spain.
Cessna MH
Department of Pathology and Intermountatin Biorepository, Intermountain Health, Salt Lake City, UT, USA.
Chang-Claude J
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.
Chen F
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Chenevix-Trench G
Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
NBCS Collaborators
No affiliation info available
Conroy DM
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Czene K
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
De Nicolo A
Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy. Institute of Oncology and Molecular Genetics, Rīga Stradiņš University, Riga, Latvia.
Domchek SM
Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Dörk T
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Dunning AM
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Eliassen AH
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.
Evans DG
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.
Fasching PA
Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
Figueroa JD
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 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.
Flyger H
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Gago-Dominguez M
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.
García-Closas M
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Glendon G
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
González-Neira A
Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Grassmann F
Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany.
Hadjisavvas A
Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Haiman CA
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Hamann U
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hart SN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Hartman MBA
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.
Ho WK
Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia. School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Selangor, Malaysia.
Hodge JM
Department of Population Science, American Cancer Society, Atlanta, GA, USA.
Hoppe R
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. University of Tübingen, Tübingen, Germany.
Howell SJ
Division of Cancer Sciences, University of Manchester, Manchester, UK.
kConFab Investigators
No affiliation info available
Jakubowska A
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.
Khusnutdinova EK
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.
Ko YD
Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany.
Kraft P
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Kristensen VN
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.
Lacey JV
Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA. City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
Li J
Human Genetics Division, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore.
Lim GH
Breast Department, KK Women's and Children's Hospital, Singapore City, Singapore. Duke-NUS Medical School, Singapore City, Singapore.
Lindström S
Department of Epidemiology, University of Washington, Seattle, WA, USA. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Lophatananon A
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.
Luccarini C
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Mannermaa A
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.
Martinez ME
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.
Mavroudis D
Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
Milne RL
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.
Muir K
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.
Nathanson KL
Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Nuñez-Torres R
Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Obi N
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.
Olson JE
Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
Palmer JR
Slone Epidemiology Center, Boston University, Boston, MA, USA. School of Medicine, Boston University, Boston, MA, USA.
Panayiotidis MI
Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS, 39762, USA.
Patel AV
Department of Population Science, American Cancer Society, Atlanta, GA, USA.
Pharoah PDP
Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
Polley EC
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
Rashid MU
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
Ruddy KJ
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Saloustros E
Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Sawyer EJ
School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
Schmidt MK
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.
Southey MC
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
Tan VK
Duke-NUS Medical School, Singapore City, Singapore. 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.
Teo SH
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.
Teras LR
Department of Population Science, American Cancer Society, Atlanta, GA, USA.
Torres D
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
Trentham-Dietz A
Carbone Cancer Center and Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Truong T
Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
Vachon CM
Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
Wang Q
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Weitzel JN
University of Kansas Cancer Center, Kansas City, KS, USA.
Yadav S
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Yao S
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Institute, Buffalo, NY, USA.
Zirpoli GR
Slone Epidemiology Center, Boston University, Boston, MA, USA.
Cline MS
UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.
Devilee P
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Tavtigian SV
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.
Goldgar DE
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
Couch FJ
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Easton DF
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Spurdle AB
Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Michailidou K
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. kyriakimi@cing.ac.cy.

MeSH

HumansFemaleCase-Control StudiesBRCA2 ProteinBreast NeoplasmsBRCA1 ProteinGenetic Predisposition to DiseaseGenetic TestingGerm-Line MutationMiddle Aged

Pub Type(s)

Journal Article

Language

eng

PubMed ID

40413188

Citation

Zanti, Maria, et al. "Analysis of More Than 400,000 Women Provides Case-control Evidence for BRCA1 and BRCA2 Variant Classification." Nature Communications, vol. 16, no. 1, 2025, p. 4852.
Zanti M, O'Mahony DG, Parsons MT, et al. Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. Nat Commun. 2025;16(1):4852.
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., ... Michailidou, K. (2025). Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. Nature Communications, 16(1), 4852. https://doi.org/10.1038/s41467-025-59979-6
Zanti M, et al. Analysis of More Than 400,000 Women Provides Case-control Evidence for BRCA1 and BRCA2 Variant Classification. Nat Commun. 2025 May 25;16(1):4852. PubMed PMID: 40413188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. AU - Zanti,Maria, AU - O'Mahony,Denise G, AU - Parsons,Michael T, AU - Dorling,Leila, AU - Dennis,Joe, AU - Boddicker,Nicholas J, AU - Chen,Wenan, AU - Hu,Chunling, AU - Naven,Marc, AU - Yiangou,Kristia, AU - Ahearn,Thomas U, AU - Ambrosone,Christine B, AU - Andrulis,Irene L, AU - Antoniou,Antonis C, AU - Auer,Paul L, AU - Baynes,Caroline, AU - Bodelon,Clara, AU - Bogdanova,Natalia V, AU - Bojesen,Stig E, AU - Bolla,Manjeet K, AU - Brantley,Kristen D, AU - Camp,Nicola J, AU - Campbell,Archie, AU - Castelao,Jose E, AU - Cessna,Melissa H, AU - Chang-Claude,Jenny, AU - Chen,Fei, AU - Chenevix-Trench,Georgia, AU - ,, AU - Conroy,Don M, AU - Czene,Kamila, AU - De Nicolo,Arcangela, AU - Domchek,Susan M, AU - Dörk,Thilo, AU - Dunning,Alison M, AU - Eliassen,A Heather, AU - Evans,D Gareth, AU - Fasching,Peter A, AU - Figueroa,Jonine D, AU - Flyger,Henrik, AU - Gago-Dominguez,Manuela, AU - García-Closas,Montserrat, AU - Glendon,Gord, AU - González-Neira,Anna, AU - Grassmann,Felix, AU - Hadjisavvas,Andreas, AU - Haiman,Christopher A, AU - Hamann,Ute, AU - Hart,Steven N, AU - Hartman,Mikael B A, AU - Ho,Weang-Kee, AU - Hodge,James M, AU - Hoppe,Reiner, AU - Howell,Sacha J, AU - ,, AU - Jakubowska,Anna, AU - Khusnutdinova,Elza K, AU - Ko,Yon-Dschun, AU - Kraft,Peter, AU - Kristensen,Vessela N, AU - Lacey,James V, AU - Li,Jingmei, AU - Lim,Geok Hoon, AU - Lindström,Sara, AU - Lophatananon,Artitaya, AU - Luccarini,Craig, AU - Mannermaa,Arto, AU - Martinez,Maria Elena, AU - Mavroudis,Dimitrios, AU - Milne,Roger L, AU - Muir,Kenneth, AU - Nathanson,Katherine L, AU - Nuñez-Torres,Rocio, AU - Obi,Nadia, AU - Olson,Janet E, AU - Palmer,Julie R, AU - Panayiotidis,Mihalis I, AU - Patel,Alpa V, AU - Pharoah,Paul D P, AU - Polley,Eric C, AU - Rashid,Muhammad U, AU - Ruddy,Kathryn J, AU - Saloustros,Emmanouil, AU - Sawyer,Elinor J, AU - Schmidt,Marjanka K, AU - Southey,Melissa C, AU - Tan,Veronique Kiak-Mien, AU - Teo,Soo Hwang, AU - Teras,Lauren R, AU - Torres,Diana, AU - Trentham-Dietz,Amy, AU - Truong,Thérèse, AU - Vachon,Celine M, AU - Wang,Qin, AU - Weitzel,Jeffrey N, AU - Yadav,Siddhartha, AU - Yao,Song, AU - Zirpoli,Gary R, AU - Cline,Melissa S, AU - Devilee,Peter, AU - Tavtigian,Sean V, AU - Goldgar,David E, AU - Couch,Fergus J, AU - Easton,Douglas F, AU - Spurdle,Amanda B, AU - Michailidou,Kyriaki, Y1 - 2025/05/25/ PY - 2024/9/2/received PY - 2025/5/7/accepted PY - 2025/5/25/medline PY - 2025/5/25/pubmed PY - 2025/5/24/entrez PY - 2025/5/25/pmc-release SP - 4852 EP - 4852 JF - Nature communications JO - Nat Commun VL - 16 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/40413188/Analysis_of_more_than_400 DB - PRIME DP - Unbound Medicine ER -
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