ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.191G>A (p.Cys64Tyr) (rs55851803)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077501 SCV001161551 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Invitae RCV000047641 SCV000075654 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 64 of the BRCA1 protein (p.Cys64Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary breast and ovarian cancer in two families (PMID: 15131401), and has been observed in numerous individuals with breast and/or ovarian cancer (PMID: 22034289, 23397983, 18489799, 19949876, 25085752). ClinVar contains an entry for this variant (Variation ID: 54400). Experimental studies have shown that this missense change abolishes E3 ubiquitin ligase activity (PMID: 11320250). This missense change is located at a functionally conserved residue within the RING domain of the BRCA1 protein (PMID: 8944023, 11526114), and a significant number of previously reported BRCA1 missense mutations have been found at this residue (PMID: 7894491, 19287957, 24516540, 23161852). Based on multifactorial likelihood algorithms using individuals' personal and family history of cancer, this variant has been determined to have a high probability of being pathogenic (PMID: 25085752, 18418466). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131896 SCV000186951 pathogenic Hereditary cancer-predisposing syndrome 2018-04-12 criteria provided, single submitter clinical testing The p.C64Y pathogenic mutation (also known as c.191G>A), located in coding exon 3 of the BRCA1 gene, results from a G to A substitution at nucleotide position 191. The cysteine at codon 64 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C64Y mutation has been detected in multiple families with hereditary breast and ovarian cancer (Shih H et al. Clin Cancer Res. 2000;6:4259-4264; Machackova E et al. BMC Cancer 2008 ;8:140; Stegel V et al. BMC Med. Genet. 2011;12:9; Krajc M et al. Clin. Genet. 2014 Jan; 85(1):59-63; Zhang J et al. Breast Cancer Res. Treat. 2012 Jul;134(2):889-94; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). This alteration is located in the highly conserved 5' RING domain and has been shown to result in abolished ubiquitin protein ligase activity (Ruffner H et al.Proc Natl Acad Sci USA. 2001 Apr 24;98(9):5134-9). Additionally, two other mutations impacting this codon (p.C64R and p.C64G) have been reported as pathogenic (Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, p.C64Y is classified as a pathogenic mutation.
GeneDx RCV000236464 SCV000292502 pathogenic not provided 2017-11-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.191G>A at the cDNA level, p.Cys64Tyr (C64Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). Using alternate nomenclature, this variant has been previously published as BRCA1 310G>A. BRCA1 Cys64Tyr has been observed in several breast and/or ovarian cancer families (Taylor 1998, Laplace-Marieze 1999, Shih 2000, Krajc 2008, Stegel 2011, Zhang 2012, Novakovic 2012, Krajc 2014). Additionally, this variant has been shown to inactivate BRCA1 ubiquitin protein ligase activity (Ruffner 2001). BRCA1 Cys64Tyr was not observed in large population cohorts (Lek 2016). Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Cys64Tyr is located at a ubiquitination site in the RING finger domain and within the BRD7 and BARD1 binding domains (Wu 1996, Narod 2004, Harte 2010, Paul 2014). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the current evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077501 SCV000325182 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236464 SCV000600273 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing
Counsyl RCV000077501 SCV000677635 likely pathogenic Breast-ovarian cancer, familial 1 2016-11-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131896 SCV000911053 pathogenic Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047641 SCV000918679 pathogenic Hereditary breast and ovarian cancer syndrome 2021-03-28 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.191G>A (p.Cys64Tyr) results in a non-conservative amino acid change located in the RING domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250804 control chromosomes. c.191G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in a loss of homology directed repair (HDR) activity. Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=9 including the expert panel)/likely pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236464 SCV001249216 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000077501 SCV001439390 pathogenic Breast-ovarian cancer, familial 1 2020-02-28 criteria provided, single submitter research ACMG codes:PS3; PS4; PM2; PP3; PP5
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000077501 SCV001499630 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001660180 SCV001878116 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077501 SCV000109301 pathogenic Breast-ovarian cancer, familial 1 2013-05-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077501 SCV000144599 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047641 SCV000587029 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077501 SCV000733678 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077501 SCV001242528 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Human Genetics - Radboudumc,Radboudumc RCV000236464 SCV001959431 pathogenic not provided no assertion criteria provided clinical testing

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