ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5165C>A (p.Ser1722Tyr) (rs80357104)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000582258 SCV000688544 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-22 criteria provided, single submitter clinical testing
Invitae RCV000637560 SCV000759024 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 1722 of the BRCA1 protein (p.Ser1722Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 491098). This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 30209399). This variant disrupts the p.Ser1722 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20516115, 12496477, 25085752). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics RCV000582258 SCV001185556 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-05 criteria provided, single submitter clinical testing The p.S1722Y variant (also known as c.5165C>A), located in coding exon 17 of the BRCA1 gene, results from a C to A substitution at nucleotide position 5165. The serine at codon 1722 is replaced by tyrosine, an amino acid with dissimilar properties. One functional study found that this nucleotide substitution is predicted to have a intermediate impact on function in a high throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In a different functional study, this variant had wildtype homologous repair activity, but also had poorly solubility due to aggregation in E coli thus was not ascertained for stability (Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69). A close match alteration, BRCA2 p.S1722F, is considered a pathogenic mutation with a severe impact on protein stability, also had intermediate activity in the high throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants, including BRCA2 p.S1722F (Wu Q et al. Mol. Cell, 2016 Feb;61:434-448). In addition, this variant segregated with breast and ovarian cancer in one family tested at this laboratory (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Brotman Baty Institute,University of Washington RCV001077730 SCV001243707 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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