Submissions for variant NM_058216.3(RAD51C):c.121G>A (p.Val41Met)

gnomAD frequency: 0.00001  dbSNP: rs879254131

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583921	SCV000691219	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 41 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 RAD51C-related disorders in the literature. This variant has been identified in 2/251432 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.
Ambry Genetics	RCV000583921	SCV001170604	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	The p.V41M variant (also known as c.121G>A), located in coding exon 1 of the RAD51C gene, results from a G to A substitution at nucleotide position 121. The valine at codon 41 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001056321	SCV001220760	uncertain significance	Fanconi anemia complementation group O	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 41 of the RAD51C protein (p.Val41Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 492361). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328424	SCV001519547	uncertain significance	not specified	2021-03-12	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.121G>A (p.Val41Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251432 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.121G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001770535	SCV002001697	uncertain significance	not provided	2020-01-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001770535	SCV002047038	uncertain significance	not provided	2021-05-05	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315439	SCV004015191	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing	The p.Val41Met variant located in coding exon 1 of the RAD51C gene, results from a G to A substitution at nucleotide position 121. The valine at codon 41 is replaced by methionine, This amino acid position is not conserved (PhyloP=0). This variant not present in our local database nor was it identified in the Genome Aggregation Database The computational analyses (PolyPhen-2, SIFT, MutationTaster) do not suggest a high pathogenic impacts on the protein; however, this information is not predictive enough to rule out pathogenicity. ClinVar has an entry (492361) for this variant reported as uncertain significance from six diffrent diagnostic labs .. Since supporting evidence is limited at this time, this variant is classified as of uncertain significance.