Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV000582258 | SCV000688544 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-06-22 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000637560 | SCV000759024 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2023-03-10 | 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: 30209399). 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: 491098). 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 tyrosine, which is neutral and polar, at codon 1722 of the BRCA1 protein (p.Ser1722Tyr). 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: 12496477, 20516115, 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 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. |
Ambry Genetics | RCV000582258 | SCV001185556 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-27 | 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. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
MGZ Medical Genetics Center | RCV001077730 | SCV002578947 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2022-08-10 | criteria provided, single submitter | clinical testing | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000637560 | SCV004227961 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2024-01-05 | criteria provided, single submitter | curation | . According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): LOF in Findlay GM et al. Nature, 2018 10;562:217-222, Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69, PM2 (supporting pathogenic): not in gnomAD, PP1 (supporting pathogenic): Parsons et al. Segregation LR 4.84 (PP1_mod) |
Brotman Baty Institute, |
RCV001077730 | SCV001243707 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |