ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population, 0.000004 (1/251296 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51C), 31206626 (2019)) as well as in individuals without cancer (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51C), 31422574 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces glycine with alanine at codon 112 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 individual affected with breast cancer and in an individual from a suspected hereditary breast and ovarian cancer family (PMID: 26822949, 31422574). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000112). This variant has been identified in 1/251296 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.

Not observed at significant frequency in large population cohorts (gnomAD); 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: 31422574, 26822949, 31206626, 35264596, 26691941, 14704354)

Variant summary: RAD51C c.335G>C (p.Gly112Ala) results in a non-conservative amino acid change to a well-conserved residue located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.335G>C has been reported in the literature in individuals affected with breast cancer without strong evidence for causality (Lhota_2016, Guindalini_2021, Weitzel_2019). 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. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, classifying it as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 112 of the RAD51C protein (p.Gly112Ala). This variant is present in population databases (rs370212314, gnomAD 0.0009%). 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: 142093). 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.