Submissions for variant NM_058216.3(RAD51C):c.253T>C (p.Cys85Arg)

gnomAD frequency: 0.00001  dbSNP: rs1060502595

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000534436	SCV000650011	uncertain significance	Fanconi anemia complementation group O	2023-09-18	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 471440). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 85 of the RAD51C protein (p.Cys85Arg).
Ambry Genetics	RCV000565022	SCV000667136	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-22	criteria provided, single submitter	clinical testing	The p.C85R variant (also known as c.253T>C), located in coding exon 2 of the RAD51C gene, results from a T to C substitution at nucleotide position 253. The cysteine at codon 85 is replaced by arginine, an amino acid with highly dissimilar 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.
GeneDx	RCV002509432	SCV002818860	uncertain significance	not provided	2022-07-07	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)
Color Diagnostics, LLC DBA Color Health	RCV000565022	SCV004357104	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 85 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 hereditary cancer in the literature. This variant has not been identified 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.