ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5143A>T (p.Ser1715Cys) (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 2020-09-23 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. Note that this alteration is also referred to as 5262A>T in published literature. 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). 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 uncertain significance not provided 2016-03-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5143A>T at the cDNA level, p.Ser1715Cys (S1715C) at the protein level, and results in the change of a Serine to a Cysteine (AGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA1 5262A>T. This variant was predicted to be destabilizing to the protein due to the formation of inclusion bodies in E. coli. (Rowling 2010). However, additional in vitro functional analyses suggest that BRCA1 Ser1715Cys has only a mild impact on protein folding, normal binding activity, uncertain binding specificity, and compromised transcriptional activity (Lee 2010). BRCA1 Ser1715Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1715Cys occurs at a position that is conserved in mammals and is located in the BRCT1 domain as well as a region known to interact with multiple other proteins (UniProt, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1715Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280538 SCV000699207 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-12-12 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). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Both 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 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-09-14 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1715 of the BRCA1 protein (p.Ser1715Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55415). Experimental studies do not agree on the impact of this missense change on BRCA1 protein function (PMID: 25748678, 20516115, 20378548, 30209399). This variant disrupts the p.Ser1715 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 11157798, 22856468), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112506 SCV000145328 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112506 SCV001241765 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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