Submissions for variant NM_058216.3(RAD51C):c.370T>A (p.Cys124Ser)

gnomAD frequency: 0.00001  dbSNP: rs1273995533

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587899	SCV000699806	uncertain significance	not specified	2019-02-08	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.370T>A (p.Cys124Ser) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, 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 8.2e-06 in 245370 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.370T>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000804815	SCV000944746	uncertain significance	Fanconi anemia complementation group O	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 124 of the RAD51C protein (p.Cys124Ser). 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: 496503). 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.
Ambry Genetics	RCV001020945	SCV001182493	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	clinical testing	The p.C124S variant (also known as c.370T>A), located in coding exon 2 of the RAD51C gene, results from a T to A substitution at nucleotide position 370. The cysteine at codon 124 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003317293	SCV004021662	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14704354)
PreventionGenetics, part of Exact Sciences	RCV003403378	SCV004120878	uncertain significance	RAD51C-related condition	2023-05-17	criteria provided, single submitter	clinical testing	The RAD51C c.370T>A variant is predicted to result in the amino acid substitution p.Cys124Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/17-56772516-T-A). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/496503/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.