Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000229310 | SCV000289760 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-10 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 753 of the BRCA1 protein (p.Ser753Asn). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 240782). 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 with a negative predictive value of 95%. 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. |
Color Diagnostics, |
RCV000772153 | SCV000905260 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-23 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with asparagine at codon 753 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer and a pancreatic cancer case-control study in 1 unaffected individual each and absent in cancer cases (PMID: 30287823, 32980694). This variant has been identified in 1/251204 chromosomes 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. |
Ambry Genetics | RCV000772153 | SCV002733341 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-17 | criteria provided, single submitter | clinical testing | The p.S753N variant (also known as c.2258G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2258. The serine at codon 753 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 0 in 7051 unselected breast cancer patients and 0.00009 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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, |
RCV000772153 | SCV003847809 | 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). |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003477832 | SCV004222593 | uncertain significance | not provided | 2023-04-22 | criteria provided, single submitter | clinical testing | The variant has not been reported in individuals affected with BRCA1-related disease in the published literature. The frequency of this variant in the general population, 0.000004 (1/251204 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. |