ClinVar Genomic variation as it relates to human health

Variant summary: The variant, RAD51C c.956G>A (p.Arg319Gln) results in a conservative amino acid change located in the C-terminal domain (IPR013632) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 246074 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.956G>A, has been reported in the literature in a patient affected with epithelial ovarian cancer, but was also found in a healthy control individual (Song 2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has classified the variant as likely benign, and the other as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with ovarian cancer (Song 2015); This variant is associated with the following publications: (PMID: 26261251, 14704354)

This missense variant replaces arginine with glutamine at codon 319 of the RAD51C 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 an ovarian case-control study in 1/3429 cases and 1/2772 unaffected individuals (PMID: 26261251) and in a pancreatic cancer case-control study in 2/23705 unaffected individuals and absent in 1005 cases (PMID: 32980694). This variant has been identified in 5/246074 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 sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 319 of the RAD51C protein (p.Arg319Gln). This variant is present in population databases (rs367846829, gnomAD 0.007%). This missense change has been observed in individual(s) with ovarian cancer and/or breast cancer (PMID: 26261251, 34326862). ClinVar contains an entry for this variant (Variation ID: 478615). 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 RAD51C protein function with a negative predictive value of 80%. 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.

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.