ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5770A>G (p.Ile1924Val)

gnomAD frequency: 0.00001  dbSNP: rs779020831
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000230760 SCV000283272 uncertain significance Hereditary breast ovarian cancer syndrome 2025-01-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1924 of the BRCA2 protein (p.Ile1924Val). This variant is present in population databases (rs779020831, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 236882). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 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.
Ambry Genetics RCV002354630 SCV002653094 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-12 criteria provided, single submitter clinical testing The p.I1924V variant (also known as c.5770A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5770. The isoleucine at codon 1924 is replaced by valine, an amino acid with highly similar properties. 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, University of Washington RCV002354630 SCV003849093 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 RCV003477784 SCV004220470 uncertain significance not provided 2023-09-16 criteria provided, single submitter clinical testing In the published literature, this variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in individuals with BRCA2-related disorders. The frequency of this variant in the general population, 0.000026 (3/113398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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.
All of Us Research Program, National Institutes of Health RCV004804943 SCV005424501 uncertain significance BRCA2-related cancer predisposition 2024-03-24 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 1924 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 3/250706 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.

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