Submissions for variant NM_000179.3(MSH6):c.1420G>C (p.Val474Leu)

dbSNP: rs1558661621

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773765	SCV000907465	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 474 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate cancer (doi: 10.1101/2021.04.15.21255554). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001373902	SCV001570641	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 474 of the MSH6 protein (p.Val474Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 629077). 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 MSH6 protein function with a negative predictive value of 95%. 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.
Mendelics	RCV003492166	SCV004232563	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000773765	SCV006030266	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-21	criteria provided, single submitter	clinical testing	The p.V474L variant (also known as c.1420G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1420. The valine at codon 474 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in 1 of 1682 Brazilian patients referred for hereditary cancer panel testing (de Oliveira JM et al. Eur J Hum Genet, 2022 Jul;30:818-823).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.