ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.190T>G (p.Cys64Gly) (rs80357064)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047634 SCV000075647 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 64 of the BRCA1 protein (p.Cys64Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs80357064, ExAC 0.02%). This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 26689913, 9042907, 7894491). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17660). Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 20103620, 23161852). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (26689913, 12915465). This variant disrupts the p.Cys64 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24516540, 22034289, 18489799, 11320250). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000129894 SCV000184711 pathogenic Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing The p.C64G pathogenic mutation (also known as c.190T>G), located in coding exon 3 of the BRCA1 gene, results from a T to G substitution at nucleotide position 190. The cysteine at codon 64 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration was first described in an African American kindred with multiple cases of early-onset breast and ovarian cancer and segregated with disease (Castilla LH et al. Nat Genet. 1994 Dec;8:387-91). It has also been identified in two family members with early-onset triple-negative breast cancers and additional family history of breast and/or ovarian cancer (Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153:201-9). In vitro studies show that this alteration can disrupt a putative exonic splicing enhancer motif and activate a cryptic 5' splice site in coding exon 4. This would result in a predicted 22-nucleotide deletion and a severely truncated protein consisting of only 63 amino acids (Yang Y et al. Hum. Mol. Genet 2003 Sep;12:2121-31; Willems P et al. Int. J. Oncol. 2009 Apr;34:1005-15; Mucaki EJ et al. Hum. Mutat. 2011 Jul;32:735-42). Additionally, this alteration has been classified as deleterious by an alternative functional mechanism resulting from disruption of a zinc-binding ring finger residue at this position. Several independent DNA repair assays showed loss of function in p.C64G point mutants for BRCA1 ubiquitin ligase activity, homology directed recombination, and functional complementation (Morris JR et al. Hum. Mol. Genet. 2006 Feb;15:599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lu C et al. Nat Commun 2015 Dec;6:10086; Starita LM et al. Genetics. 2015 Jun;200:413-22). This alteration is also referred to as 309T>G in published literature. Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000235121 SCV000210068 pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.190T>G at the cDNA level, p.Cys64Gly (C64G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). This variant, also reported as BRCA1 309T>G using alternate nomenclature, has been observed in individuals with familial breast and/or ovarian cancer (Castilla 1994, Breast Cancer Linkage Consortium 1997, Churpek 2015, Lynce 2015). Functional assays have shown that this variant results in defective homologous recombination and single-strand annealing repair, impacts BARD1 binding, and abrogates ubiquitin ligase activity (Wu 1996, Brzovic 2003, Ransburgh 2010, Bouwman 2013, Towler 2013, Lu 2015). BRCA1 Cys64Gly was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Cys64Gly occurs at a position that is conserved across species and is located within an active-site Cysteine within the RING finger domain and a region known to interact with multiple proteins (Wu 1996, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on current evidence, we consider this variant to be pathogenic.
Counsyl RCV000019228 SCV000221114 pathogenic Breast-ovarian cancer, familial 1 2015-02-04 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000019228 SCV000296366 pathogenic Breast-ovarian cancer, familial 1 2015-07-18 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019228 SCV000325177 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047634 SCV000698899 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.190T>G (p.Cys64Gly) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing (Yang_2003). The variant allele was found at a frequency of 4.1e-06 in 246068 control chromosomes (gnomAD and publications). This variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Castilla_1994, Lynce_2015, Tung_2015, Shih_2000, Serova_1997). These data indicate that the variant is very likely to be associated with disease. Functional studies using HeLa cells confirmed this variant to be deleterious by using homology-directed recombination (HDR) and single-strand annealing (SSA) assays (Ransburgh_2010, Towler_2013). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235121 SCV000888856 pathogenic not provided 2020-01-08 criteria provided, single submitter clinical testing The best available variant frequency is above the disease allele frequency. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Strong co-segregation with disease in affected individuals from a single family.
Color Health, Inc RCV000129894 SCV000905209 pathogenic Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing
OMIM RCV000019228 SCV000039516 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019228 SCV000109300 pathogenic Breast-ovarian cancer, familial 1 2011-06-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019228 SCV000144597 uncertain significance 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 RCV000496255 SCV000587028 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000019228 SCV001241647 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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