ClinVar Genomic variation as it relates to human health

Variant summary: RAD51C c.635G>A (p.Arg212His) results in a non-conservative amino acid change located in the ATP-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 252186 control chromosomes (gnomAD and publication). The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), suggesting that the variant may be benign. c.635G>A has been reported in the literature in individuals affected with cancer including breast cancer, Lynch syndrome and cutaneous melanoma (e.g. Pang_2011, Wong_2015, Yurgelun_2015, Pritchard_2018, Wang_2019, Kwong_2020, Akcay_2021, Krivokuca_2021, Lim_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced cell viability and double-strand break repair (Kolinjivadi et al., 2022); Observed in individuals with breast cancer or other cancers, but also observed in controls (Pang et al., 2011; Yurgelun et al., 2015; Wong et al., 2016; Pritchard et al., 2018; Wang et al., 2019; Kwong et al., 2020; Akcay et al., 2020; Dorling et al., 2021; Kolinjivadi et al., 2022; Lim et al., 2022; Zheng et al., 2022); This variant is associated with the following publications: (PMID: 29263802, 25980754, 21597919, 25338684, 34426522, 14704354, 34284872, 32566746, 36562461, 33471991, 29641532, 30982232, 32068069, 32658311, 35057767, 35039523)

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

This missense variant replaces arginine with histidine at codon 212 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 21597919, 25980754). This variant has been identified in 25/282612 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In a large breast cancer case-control study, this variant was observed in 9/60466 cases and 10/53461 unaffected controls, and did not show significant association with breast cancer (OR=0.796; 95%CI 0.323 to 1.958; p-value=0.652) (Leiden Open Variation Database DB-ID RAD51C_000069, PMID: 33471991). 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 histidine, which is basic and polar, at codon 212 of the RAD51C protein (p.Arg212His). This variant is present in population databases (rs200857129, gnomAD 0.09%). This missense change has been observed in individual(s) with breast cancer and clinical features of Lynch syndrome (PMID: 21597919, 25980754, 29263802, 36562461). ClinVar contains an entry for this variant (Variation ID: 187633). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAD51C function (PMID: 36562461). 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.