PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

Basser Center for BRCA Abramson Cancer Center Penn Medicine University of Pennsylvania Philadelphia PA

Cancer Control and Population Science Huntsman Cancer Institute University of Utah Salt Lake City UT

Cancer Control and Population Science Huntsman Cancer Institute University of Utah Salt Lake City UT; Department of Dermatology University of Utah School of Medicine Salt Lake City UT

Cancer Genetics Centre Hong Kong Sanatorium and Hospital Happy Valley Hong Kong; Department of Surgery LKS Faculty of Medicine University of Hong Kong Pok Fu Lam Hong Kong

Center for Cancer Genetics and Prevention Dana Farber Cancer Institute Boston MA

Center for Clinical Cancer Genetics The University of Chicago Chicago IL

Center for Hereditary Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany; Center for Integrated Oncology Faculty of Medicine University of Cologne Cologne Germany

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care School of Clinical Medicine University of Cambridge Cambridge United Kingdom

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Victoria Australia

Clinical Cancer Research Center and Department of Clinical Genetics Aalborg University Hospital Aalborg Denmark; Department of Clinical Medicine The Faculty of Medicine Aalborg University of Aalborg Aalborg Denmark

Department of Cancer Biology and Genetics College of Medicine The Ohio State University Columbus OH

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Genetics Sygehus Lillebaelt Vejle Hospital Vejle Denmark

Department of Epidemiology and Population Health and Stanford Cancer Institute School of Medicine Stanford University Stanford CA

Department of Epidemiology Mailman School of Public Health Columbia University New York NY; Herbert Irving Comprehensive Cancer Center Columbia University New York NY

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

Department of Health Sciences Research Mayo Clinic Rochester MN

Department of Human and Medical Genetics Institute of Biomedical Sciences Faculty of Medicine Vilnius University Vilnius Lithuania; State Research Institute Centre for Innovative Medicine Vilnius Lithuania

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN

Department of Medical Genetics NIHR Cambridge Biomedical Research Centre Cambridge University Hospitals NHS Foundation Trust University of Cambridge Cambridge United Kingdom

Department of Tumor Biology Institute of Cancer Research The Norwegian Radium Hospital Oslo University Hospital Oslo Norway; Center for Hereditary Tumors HELIOS Klinikum Wuppertal University of Witten Herdecke Wuppertal Germany

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD

Divisions of Oncology and Pathology Department of Clinical Sciences Lund Lund University Lund Sweden

Faculty of Medicine University of Southampton Southampton United Kingdom

Familial Cancer Service Crown Princess Mary Cancer Centre Westmead Hospital Sydney Medical School University of Sydney Centre for Cancer Research The Westmead Institute for Medical Research Westmead New South Wales Australia

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

Fundación Pública galega Medicina Xenómica SERGAS Grupo de Medicina Xenómica USC CIBERER IDIS Santiago de Compostela Spain

Genome Diagnostics Program IFOM the FIRC Institute of Molecular Oncology Milan Italy

Immunology and Molecular Oncology Unit IOV Istituto Oncologico Veneto IRCCS Padova Italy

INBIOMED Faculty of Medicine University of Buenos Aires CONICET and Genotyping Laboratory Department of Clinical Chemistry CEMIC Buenos Aires Argentina

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

Medical Genetics Unit Department of Medical Sciences University of Torino Torino Italy

Medical Oncology Unit AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII Bergamo Italy

Medical Oncology Unit AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII Bergamo Italy; University of Siena Siena Italy

Molecular Diagnostics Aalborg University Hospital Aalborg Denmark; Clinical Cancer Research Center and Department of Clinical Genetics Aalborg University Hospital Aalborg Denmark; Department of Clinical Medicine The Faculty of Medicine Aalborg University of Aalborg Aalborg Denmark

Molecular Diagnostics Laboratory National Centre for Scientific Research Demokritos INRASTES Institute of Nuclear and Radiological Sciences and Technology Energy and Safety Athens Greece

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

Molecular Oncology Laboratory CIBERONC Hospital Clinico San Carlos Instituto de Investigación Sanitaria San Carlos Madrid Spain

Molecular Oncology Research Center Barretos Cancer Hospital São Paulo Brazil; National Cancer Institute Rio de Janeiro Brazil

NorthShore University HealthSystem University of Chicago Evanston IL

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

Parkville Familial Cancer Centre Peter MacCallum Cancer Centre Melbourne Victoria Australia; The Sir Peter MacCallum Department of Oncology Faculty of Medicine Dentistry and Health Sciences The University of Melbourne Melbourne Victoria Australia

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia; Department of Clinical Pathology Melbourne Medical School University of Melbourne Melbourne Victoria Australia; Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Service de Génétique Institut Curie Paris France; Paris Sciences and Lettres Research University Paris France

SOD Genetica Molecolare University Hospital Pisa Italy

The Sir Peter MacCallum Department of Oncology Faculty of Medicine Dentistry and Health Sciences The University of Melbourne Melbourne Victoria Australia

Unit of Hereditary Cancer IRCCS Ospedale Policlinico San Martino Genoa Italy

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori Milano Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Erratum In

Genet Med. 2022 Oct;24(10):2208. doi: 10.1016/j.gim.2022.08.005. PubMed

See more in PubMed

Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995;56(1):265–271. PubMed PMC

Antoniou AC, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117–1130. Published correction appears in Am J Hum Genet. 2003;73(3):709. 10.1086/375033. PubMed DOI PMC

Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–2416. 10.1001/jama.2017.7112. PubMed DOI

Thompson D, Easton D, Breast Cancer Linkage Consortium. Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev. 2002;11(4):329–336. PubMed

Gayther SA, Warren W, Mazoyer S, et al. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet. 1995;11(4):428–433. 10.1038/ng1295-428. PubMed DOI

Rebbeck TR, Mitra N, Wan F, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015;313(13):1347–1361. Published correction appears in JAMA. 2015;314(6):628. 10.1001/jama.2014.5985. PubMed DOI PMC

Spurdle AB, Healey S, Devereau A, et al. ENIGMA—evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat. 2012;33(1):2–7. 10.1002/humu.21628. PubMed DOI PMC

Goldgar DE, Easton DF, Deffenbaugh AM, et al. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet. 2004;75(4):535–544. 10.1086/424388. PubMed DOI PMC

Thompson D, Easton DF, Goldgar DE. A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet. 2003;73(3):652–655. 10.1086/378100. PubMed DOI PMC

Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007;81(5):873–883. 10.1086/521032. PubMed DOI PMC

Li H, LaDuca H, Pesaran T, et al. Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort. Genet Med. 2020;22(4):701–708. 10.1038/s41436-019-0729-1. PubMed DOI PMC

Spurdle AB, Couch FJ, Parsons MT, et al. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia. Breast Cancer Res. 2014;16(6):3419. 10.1186/s13058-014-0474-y. PubMed DOI PMC

Parsons MT, Tudini E, Li H, et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: an ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40(9):1557–1578. 10.1002/humu.23818. PubMed DOI PMC

Spurdle AB, Whiley PJ, Thompson B, et al. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J Med Genet. 2012;49(8):525–532. 10.1136/jmedgenet-2012-101037. PubMed DOI PMC

Moghadasi S, Meeks HD, Vreeswijk MP, et al. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet. 2018;55(1):15–20. 10.1136/jmedgenet-2017-104560. PubMed DOI

Shimelis H, Mesman RLS, Von Nicolai C, et al. BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. Cancer Res. 2017;77(11):2789–2799. 10.1158/0008-5472.CAN-16-2568. PubMed DOI PMC

ClinVar. National Center for Biotechnology Information, U.S. National Library of Medicine. http://www.ncbi.nlm.nih.gov/clinvar. Accessed July 15, 2018.

Cline MS, Liao RG, Parsons MT, et al. BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2. PLoS Genet. 2018;14(12): e1007752. 10.1371/journal.pgen.1007752. PubMed DOI PMC

Chenevix-Trench G, Milne RL, Antoniou AC, et al. An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res. 2007;9(2):104. 10.1186/bcr1670. PubMed DOI PMC

Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A. Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Hum Mutat. 2008;29(11): 1342–1354. 10.1002/humu.20896. PubMed DOI PMC

Valleé MP, Di Sera TL, Nix DA, et al. Adding in silico assessment of potential splice aberration to the integrated evaluation of BRCA gene unclassified variants. Hum Mutat. 2016;37(7):627–639. 10.1002/humu.22973. PubMed DOI PMC

Richardson ME, Hu C, Lee KY, et al. Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. Am J Hum Genet. 2021;108(3):458–468. 10.1016/j.ajhg.2021.02.005. PubMed DOI PMC

Woods NT, Baskin R, Golubeva V, et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom Med. 2016;1:16001. 10.1038/npjgenmed.2016.1. PubMed DOI PMC

Findlay GM, Daza RM, Martin B, et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018;562(7726):217–222. 10.1038/s41586-018-0461-z. PubMed DOI PMC

Walker LC, Whiley PJ, Couch FJ, et al. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat. 2010;31(6):E1484–E1505. 10.1002/humu.21267. PubMed DOI PMC

Fraile-Bethencourt E, Valenzuela-Palomo A, Díez-Gó mez B, Caloca MJ, Gó mez-Barrero S, Velasco EA. Minigene splicing assays identify 12 Spliceogenic Variants of BRCA2 Exons 14 and 15. Front Genet. 2019;10:503. 10.3389/fgene.2019.00503. PubMed DOI PMC

Caleca L, Putignano AL, Colombo M, et al. Characterization of an Italian founder mutation in the RING-finger domain of BRCA1. PLoS One. 2014;9(2):e86924. 10.1371/journal.pone.0086924. PubMed DOI PMC

Anagnostopoulos T, Pertesi M, Konstantopoulou I, et al. G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history. Breast Cancer Res Treat. 2008;110(2):377–385. 10.1007/s10549-007-9729-y. PubMed DOI

PedPro. Fishing for Gene & Proteins http://www.bjfenglab.org. Accessed September 21, 2018.

Lange K, Weeks D, Boehnke M. Programs for pedigree analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol. 1988;5(6):471–472. 10.1002/gepi.1370050611. PubMed DOI

Yang X, Leslie G, Doroszuk A, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol. 2020;38(7):674–685. 10.1200/JCO.19.01907. PubMed DOI PMC

Forman D, Bray F, Brewster DH, et al., eds. Cancer incidence in five continents. IARC Sci Publ No. 164. Lyon, France: International Agency for Research on Cancer. 2014. https://gco.iarc.fr/today/home. Accessed July 22, 2019.

Barnes DR, Rookus MA, McGuffog L, et al. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet Med. 2020;22(10):1653–1666. 10.1038/s41436-020-0862-x. PubMed DOI PMC

Terry MB, Liao Y, Kast K, et al. The influence of number and timing of pregnancies on breast cancer risk for women with BRCA1 or BRCA2 mutations. JNCI Cancer Spectr. 2018;2(4):pky078. 10.1093/jncics/pky078. PubMed DOI PMC

Antoniou AC, Cunningham AP, Peto J, et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer. 2008;98(8):1457–1466. Published correction appears in Br J Cancer. 2008;98(12):2015. 10.1038/sj.bjc.6604305. PubMed DOI PMC

Guidugli L, Carreira A, Caputo SM, et al. Functional assays for analysis of variants of uncertain significance in BRCA2. Hum Mutat. 2014;35(2):151–164. 10.1002/humu.22478. PubMed DOI PMC

Amos CI, Dennis J, Wang Z, et al. The OncoArray consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiol Biomarkers Prev. 2017;26(1):126–135. 10.1158/1055-9965.EPI-16-0106. PubMed DOI PMC

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk