Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000549570 | SCV000635868 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 939 of the BRCA1 protein (p.Val939Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 462594). 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001284539 | SCV001470380 | uncertain significance | not provided | 2023-07-26 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been described to occur in a region in the BRCA1 gene where pathogenic missense variants are infrequent, known as a "coldspot" (PMID: 31911673 (2020)). This variant 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
Ambry Genetics | RCV002438340 | SCV002747648 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-03 | criteria provided, single submitter | clinical testing | The p.V939I variant (also known as c.2815G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2815. The valine at codon 939 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly 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, |
RCV002438340 | SCV003849333 | 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). |