Submissions for variant NM_000179.3(MSH6):c.2197A>G (p.Met733Val)

dbSNP: rs1355166868

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572098	SCV000676132	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-02	criteria provided, single submitter	clinical testing	The p.M733V variant (also known as c.2197A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2197. The methionine at codon 733 is replaced by valine, an amino acid with highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818585	SCV000959205	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-04-12	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 486901). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 733 of the MSH6 protein (p.Met733Val). 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 MSH6-related conditions.
Color Diagnostics, LLC DBA Color Health	RCV000572098	SCV001735161	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 733 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 one individual from a predominantly colorectal and endometrial cancer cohort (PMID: 31391288). This variant has been identified in 1/250894 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.
All of Us Research Program, National Institutes of Health	RCV004001196	SCV004836218	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 733 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 one individual from a predominantly colorectal and endometrial cancer cohort (PMID: 31391288). This variant has been identified in 1/250894 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.