Submissions for variant NM_058216.3(RAD51C):c.622A>G (p.Ile208Val)

gnomAD frequency: 0.00001  dbSNP: rs771078849

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230917	SCV000291236	uncertain significance	Fanconi anemia complementation group O	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 208 of the RAD51C protein (p.Ile208Val). This variant is present in population databases (rs771078849, gnomAD 0.003%). This missense change has been observed in individual(s) with RAD51C-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 241773). 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	RCV000568792	SCV000663759	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	The p.I208V variant (also known as c.622A>G), located in coding exon 4 of the RAD51C gene, results from an A to G substitution at nucleotide position 622. The isoleucine at codon 208 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1/1197 individuals that underwent analysis of 36 genes involved in hereditary cancer predisposition and was classified as a variant of unknown significance (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). 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.
Color Diagnostics, LLC DBA Color Health	RCV000568792	SCV000686367	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 208 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 been identified in 3/251238 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.
GeneKor MSA	RCV000568792	SCV000822171	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001561241	SCV001783801	uncertain significance	not provided	2019-06-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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: 31159747, 28678401)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001561241	SCV002010616	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469163	SCV004209767	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-18	criteria provided, single submitter	clinical testing