ClinVar Genomic variation as it relates to human health

Variant summary: RAD51C c.779G>A (p.Arg260Gln) results in a conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246218 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.779G>A has been reported in the literature, however 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant 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 (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge

RAD51C:c.779G>A is present in 0.00080% in the large population studies (GnomAd). The variant is predicted to create a de novo acceptor splice site in exon 5 by in silico splicing tools. Functional RNA study has shown that the variant does not cause splicing aberration (PMID: 35806449). Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PM2, PP3)

This missense variant replaces arginine with glutamine at codon 260 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251428 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 260 of the RAD51C protein (p.Arg260Gln). This variant is present in population databases (rs730881926, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 35039564). ClinVar contains an entry for this variant (Variation ID: 186692). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.