ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5143A>T (p.Ser1715Cys)

dbSNP: rs80357222
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129744 SCV000184550 likely pathogenic Hereditary cancer-predisposing syndrome 2022-11-08 criteria provided, single submitter clinical testing The p.S1715C variant (also known as c.5143A>T), located in coding exon 16 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5143. The serine at codon 1715 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration impacts a highly-conserved residue within the N-terminal BRCT functional domain of BRCA1 and has been shown to result in significantly reduced protein function in several protein functional assays (Rowling P et al. J Biol Chem. 2010 Jun 25;285(26):20080-7; Lee M et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Findlay GM et al. Nature 2018 10;562(7726):217-222). Note that this alteration is also referred to as 5262A>T in published literature. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000586760 SCV000293460 likely pathogenic not provided 2023-07-11 criteria provided, single submitter clinical testing Observed in an individual with ovarian cancer (Flaum et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5262A>T; This variant is associated with the following publications: (PMID: 20516115, 20378548, 15235020, 17305420, 12955719, 25348405, 30209399, 30765603, 28781887, 35665744, 25748678, 36169650)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280538 SCV000699207 likely pathogenic Hereditary breast ovarian cancer syndrome 2022-12-15 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5143A>T (p.Ser1715Cys) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant has been reported to have a destabilizing effect on the BRCA1 protein (Rowling_2010). The variant was absent in 251300 control chromosomes. c.5143A>T has been reported in the literature in at-least one individual affected with and/or undergoing testing for Hereditary Breast And Ovarian Cancer (Judkins_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. However, a different missense variant located at the same codon, namely p.Ser1715Asn has been reported to segregate with breast and ovarian cancer in an extended family pedigree (Campbell_2013) suggesting an impact on protein function. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of HDR capacity (Findlay_2018) and an inability to form ionization-radiation induced foci (IRIS) despite a retained ability to recruit Rad51 to sites of double stranded breaks (DSB) (Gaboriau_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely pathogenic and one classified the variant as uncertain significance. All submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586760 SCV001470179 likely pathogenic not provided 2020-07-10 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. 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. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV001280538 SCV001536379 likely pathogenic Hereditary breast ovarian cancer syndrome 2023-07-10 criteria provided, single submitter clinical testing Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20378548, 20516115, 24845084, 25748678, 30209399, 30765603). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55415). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1715 of the BRCA1 protein (p.Ser1715Cys). This variant disrupts the p.Ser1715 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 22856468). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112506 SCV000145328 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-06-20 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000112506 SCV001241765 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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