ClinVar Miner

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

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Total submissions: 15
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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 2019-12-27 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 Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification;Well-characterized mutation at same position;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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 RCV000131896 SCV000911053 pathogenic Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047641 SCV000918679 pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.191G>A (p.Cys64Tyr) variant involves the alteration of a conserved nucleotide and is located in the critical zing finger domain of BRCA1, which is known to interact with BARD1, an effector of DNA repair. 5/5 in silico tools predict a damaging outcome for this variant. Codon 64 seems to be a mutational hotspot as other missense variants, p.Cys64Gly, p.Cys64Arg and p.Cys64Trp, have been reported in patients with HBOC. This variant is absent in 245776 control chromosomes (gnomAD). The variant has been reported in numerous affected individuals and families in the literature. Two independent functional studies report this variant to cause complete loss of E3-ubiquitin ligase activity (Ruffner_2001, Brzovic_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236464 SCV001249216 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
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

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