Submissions for variant NM_058216.3(RAD51C):c.883G>A (p.Ala295Thr)

gnomAD frequency: 0.00004  dbSNP: rs746571208

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459897	SCV000550215	uncertain significance	Fanconi anemia complementation group O	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 295 of the RAD51C protein (p.Ala295Thr). This variant is present in population databases (rs746571208, gnomAD 0.03%). 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: 409854). 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	RCV000562859	SCV000667113	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	The p.A295T variant (also known as c.883G>A), located in coding exon 6 of the RAD51C gene, results from a G to A substitution at nucleotide position 883. The alanine at codon 295 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000562859	SCV000691279	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 295 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 4/251044 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.
Sema4, Sema4	RCV000562859	SCV002530026	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
GeneDx	RCV002466508	SCV002762327	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26261251, 14704354)