BRCA2 NM_000059.4:c.2353A>G, Ile785Val

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 785 of the BRCA2 protein (p.Ile785Val). This variant is present in population databases (rs747748537, gnomAD 0.006%). This missense change has been observed in individual(s) with prostate cancer (PMID: 32393398). ClinVar contains an entry for this variant (Variation ID: 462264). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 32393398). 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.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

This missense variant replaces isoleucine with valine at codon 785 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact the rescue of Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 32393398). This variant has been detected in an individual affected with prostate cancer (PMID: 32393398). This variant has been identified in 3/282226 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.