Submissions for variant NM_058216.3(RAD51C):c.769C>G (p.Leu257Val)

gnomAD frequency: 0.00007  dbSNP: rs750551012

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223013	SCV000276354	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-29	criteria provided, single submitter	clinical testing	The p.L257V variant (also known as c.769C>G), located in coding exon 5 of the RAD51C gene, results from a C to G substitution at nucleotide position 769. The leucine at codon 257 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555322	SCV000650023	uncertain significance	Fanconi anemia complementation group O	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 257 of the RAD51C protein (p.Leu257Val). This variant is present in population databases (rs750551012, gnomAD 0.01%). 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: 232264). 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.
Color Diagnostics, LLC DBA Color Health	RCV000223013	SCV001345793	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 257 of the RAD51C protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV003221868	SCV003918512	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate in vivo binding partner interactions comparable to wild type (Prakash et al., 2022); This variant is associated with the following publications: (PMID: 14704354, 36099300)