Submissions for variant NM_058216.3(RAD51C):c.934C>G (p.Arg312Gly)

dbSNP: rs730881932

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824156	SCV000965042	likely pathogenic	Fanconi anemia complementation group O	2023-09-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 665797). 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 expected to disrupt RAD51C protein function. Studies have shown that this missense change results in skipping of exon 7 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 312 of the RAD51C protein (p.Arg312Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
GeneDx	RCV001585767	SCV001811373	uncertain significance	not provided	2021-10-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek 2016); 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)
Ambry Genetics	RCV002372361	SCV002688678	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-17	criteria provided, single submitter	clinical testing	The p.R312G variant (also known as c.934C>G), located in coding exon 7 of the RAD51C gene, results from a C to G substitution at nucleotide position 934. The arginine at codon 312 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly 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.
Baylor Genetics	RCV004569786	SCV005053964	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-12-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004569786	SCV005406771	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-09-19	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].