ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 212 of the RAD51C protein (p.Arg212Cys). This variant observed in an individual with a personal and/or family history of hereditary breast and ovarian cancer (PMID: 14704354, 31742824, 36099300) also identified in 1/882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This variant is present in population databases (rs137947462, gnomAD 0.01%). ClinVar contains an entry for this variant (Variation ID: 409842). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"). 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 212 of the RAD51C protein (p.Arg212Cys). This variant is present in population databases (rs137947462, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 409842). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51C protein function. 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 missense variant replaces arginine with cysteine at codon 212 of the RAD51C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has reported that this variant does not impact RAD51C function in binding to other RAD51 paralogs and in a homology-directed repair assay (PMID: 36099300). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000156) and among individuals with personal or family history of breast, ovarian or pancreatic cancer (PMID: 31742824). This variant has been identified in 9/282638 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.

The p.R212C variant (also known as c.634C>T), located in coding exon 4 of the RAD51C gene, results from a C to T substitution at nucleotide position 634. The arginine at codon 212 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in 1/882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). Multiple functional studies on this alteration have demonstrated that it does not impact protein function (Prakash R et al. Proc Natl Acad Sci U S A 2022 Sep;119(38):e2202727119). This amino acid position is well 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 alteration remains unclear.

Observed in an individual with a personal and/or family history of hereditary breast and ovarian cancer (PMID: 31742824); Published functional studies demonstrate protein interaction with RAD51 paralog comparable to wild type (PMID: 36099300); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14704354, 36099300, 31742824)

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