Submissions for variant NM_002439.5(MSH3):c.3335C>T (p.Thr1112Met)

gnomAD frequency: 0.00001  dbSNP: rs576204286

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818993	SCV000959632	uncertain significance	not provided	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1112 of the MSH3 protein (p.Thr1112Met). This variant is present in population databases (rs576204286, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 661554). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV001020019	SCV001181442	likely benign	Hereditary cancer-predisposing syndrome	2024-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Sema4, Sema4	RCV001020019	SCV002536512	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	curation
GeneDx	RCV000818993	SCV002588088	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with esophageal cancer and pancreatic cancer (Deng et al., 2019; Pang et al., 2020); This variant is associated with the following publications: (PMID: 32636238, 30833958)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000818993	SCV004221101	uncertain significance	not provided	2024-11-09	criteria provided, single submitter	clinical testing	The MSH3 c.3335C>T (p.Thr1112Met) variant has been reported in the published literature in individuals with T-lymphoblastic leukemia (PMID: 28157215 (2017)), esophageal cancer (PMID: 30833958 (2019)), and pancreatic cancer (PMID: 32636238 (2020)). The frequency of this variant in the general population, 0.00082 (15/18348 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004751738	SCV005365566	uncertain significance	MSH3-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The MSH3 c.3335C>T variant is predicted to result in the amino acid substitution p.Thr1112Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.082% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/661554/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.