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 2020-01-08 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 at least 2 individuals affected with breast cancer and 2 individuals affected with ovarian cancer (PMID: 26689913, 9042907, 16140926). In addition, this variant has been reported to segregate with breast and/or ovarian cancer in a single family (PMID: 7894491). It was found in all 5 affected family members and not in the single unaffected relative tested. ClinVar contains an entry for this variant (Variation ID: 17660). This variant affects the highly conserved Cys64 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421). Experimental studies using RT-PCR and RNA-seq have shown that this missense change alters splicing and causes a 22 nucleotide deletion that results in BRCA1 truncation (PMID: 12915465, 26689913). In addition, in the event that this variant could be present in some full-length protein, in vitro experimental studies have shown that it cannot functionally complement BRCA1-deficient mouse embryonic stem cells and that it interferes with homology directed repair, BARD1 binding, and double-strand break repair by the single-strand annealing pathway (PMID: 20103620, 23161852, 23867111, 12732733). Different missense substitutions at this codon, p.Cys64Arg and p.Cys64Tyr, have been determined to be pathogenic (PMID: 24516540, 22034289, 18489799, 11320250). This suggests that the cysteine residue is critical for BRCA1 protein function and that other missense substitutions, such as this variant, at this position may also be pathogenic. 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 In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification;Functionally-validated splicing 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
Integrated Genetics/Laboratory Corporation of America 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 2015-07-18 criteria provided, single submitter clinical testing
Color 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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