ClinVar Genomic variation as it relates to human health

Variant summary: The c.458G>A (p.Gly153Asp) in RAD51C gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is located outside of any known functional domain. Yet, functional studies have shown that this missense change alters the ability of RAD51C protein to form a complex with XRCC1 and RAD51B. (Clague, 2011). The variant is present in the large control population dataset of ExAC at a low frequency 0.000008 (1/121372 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.00006) in this gene. The variant has been reported in at least 1 affected individuals in the literature without segregation analysis being performed. In addition, several reputable databases/clinical laboratories classify the variant as VUS. Lastly, this variant was identified in an internal specimen undergoing genetic testing together with c.1100delC in CHEK2 gene. Taken together, the variant was classified as VUS until more data become available.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25470109, 36969410, 28829762, 36099300, 14704354, 37253112, 32322110, 23117857, 21980511)

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 153 of the RAD51C protein (p.Gly153Asp). This variant is present in population databases (rs765730332, gnomAD 0.003%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21980511). ClinVar contains an entry for this variant (Variation ID: 185444). 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 expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 21980511). 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.

The p.G153D variant (also known as c.458G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 458. The glycine at codon 153 is replaced by aspartic acid, an amino acid with similar properties. This alteration has previously been reported in an individual diagnosed with breast cancer at age 60 and ovarian cancer at age 79. Functional analyses of this alteration showed little effect on RAD51C protein expression (immunoblot assay); however, it disrupted the interaction between RAD51C and RAD51B and XRCC3 in yeast two-hybrid assays (Clague J, PLoS ONE 2011 ; 6(9):e25632). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.

DNA sequence analysis of the RAD51C gene demonstrated a sequence change, c.458G>A, in exon 3 that results in an amino acid change, p.Gly153Asp. This sequence change has been previously described in an individual with breast and ovarian cancer (PMID: 21980511). Functional assays showed that this variant alters the ability of RAD51C to interact with XRCC3 and RAD51B but no significant impact on RAD51C protein expression (PMID: 21980511). This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.0008% (dbSNP rs765730332). The p.Gly153Asp change affects a highly conserved amino acid residue located in a domain of the RAD51C protein that is known to be functional. The p.Gly153Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences the clinical significance of the p.Gly153Asp change remains unknown at this time.