Submissions for variant NM_000179.3(MSH6):c.772A>G (p.Ile258Val)

gnomAD frequency: 0.00001  dbSNP: rs786202565

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165428	SCV000216157	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-21	criteria provided, single submitter	clinical testing	The p.I258V variant (also known as c.772A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 772. The isoleucine at codon 258 is replaced by valine, an amino acid with highly similar 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.
Color Diagnostics, LLC DBA Color Health	RCV000165428	SCV001357804	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 258 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001308320	SCV001497765	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-07-16	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 258 of the MSH6 protein (p.Ile258Val). 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: 185923). 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.
GeneDx	RCV002284369	SCV002574622	uncertain significance	not provided	2022-09-13	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
Baylor Genetics	RCV003462171	SCV004195803	uncertain significance	Endometrial carcinoma	2024-02-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004786466	SCV005402203	uncertain significance	Lynch syndrome 5	2024-02-13	criteria provided, single submitter	clinical testing	The MSH6 c.772A>G (p.Ile258Val) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.