Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000637408 | SCV000758864 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-06-18 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 531244). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 645 of the BRCA1 protein (p.Ser645Cys). |
| Ambry Genetics | RCV001013643 | SCV001174256 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-20 | criteria provided, single submitter | clinical testing | The p.S645C variant (also known as c.1934C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1934. The serine at codon 645 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| University of Washington Department of Laboratory Medicine, |
RCV001013643 | SCV003849620 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
| All of Us Research Program, |
RCV004003842 | SCV004818251 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with cysteine at codon 645 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV005000416 | SCV005626022 | uncertain significance | not provided | 2023-10-31 | criteria provided, single submitter | clinical testing | The BRCA1 c.1934C>G (p.Ser645Cys) variant has not been reported in individuals with BRCA1-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |