Submissions for variant NM_000179.3(MSH6):c.818G>T (p.Gly273Val)

dbSNP: rs769610487

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232347	SCV000283858	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561246	SCV000669949	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The p.G273V variant (also known as c.818G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 818. The glycine at codon 273 is replaced by valine, an amino acid with dissimilar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and normal mismatch repair expression by immunohistochemistry (Yang RK et al. Cancers (Basel), 2022 Sep;14). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000561246	SCV000685521	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 273 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). 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 1/251030 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.
Mendelics	RCV003491994	SCV001135795	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561246	SCV002536355	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-04	criteria provided, single submitter	curation
GeneDx	RCV003233509	SCV003930940	uncertain significance	not provided	2023-06-05	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; Observed in an individual with endometrial carcinoma, which showed high microsatellite instability and proficient mismatch repair ability (Yang et al., 2022); This variant is associated with the following publications: (PMID: 33827469, 36230473)
Baylor Genetics	RCV003463644	SCV004195562	uncertain significance	Endometrial carcinoma	2023-12-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998733	SCV004837085	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 273 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). 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 1/251030 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003233509	SCV005623524	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	The MSH6 c.818G>T (p.Gly273Val) variant has been reported in the published literature in an individual with endometrial carcinoma whose tumor demonstrated high microsatellite instability and normal mismatch repair function (PMID: 36230473 (2022)). It was also reported in an individual with breast cancer with a family history of both breast and prostate cancers (PMID: 35534704 (2022)), as well as in an individual with an unspecified cancer (PMID: 33827469 (2021)). The frequency of this variant in the general population, 0.000004 (1/251030 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on MSH6 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000582421	SCV000691921	uncertain significance	not specified		no assertion criteria provided	clinical testing