Submissions for variant NM_058216.3(RAD51C):c.473T>C (p.Ile158Thr)

dbSNP: rs1394901462

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545165	SCV000660339	uncertain significance	Fanconi anemia complementation group O	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 158 of the RAD51C protein (p.Ile158Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 478578). 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. 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	RCV000777209	SCV000912900	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 158 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251464 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.
Ambry Genetics	RCV000777209	SCV001184777	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-29	criteria provided, single submitter	clinical testing	The p.I158T variant (also known as c.473T>C), located in coding exon 3 of the RAD51C gene, results from a T to C substitution at nucleotide position 473. The isoleucine at codon 158 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.