Submissions for variant NM_002439.5(MSH3):c.1366G>A (p.Glu456Lys)

gnomAD frequency: 0.00001  dbSNP: rs963234468

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814730	SCV000955152	uncertain significance	not provided	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 456 of the MSH3 protein (p.Glu456Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 658005). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV001011065	SCV001171344	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	The p.E456K variant (also known as c.1366G>A), located in coding exon 9 of the MSH3 gene, results from a G to A substitution at nucleotide position 1366. The glutamic acid at codon 456 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly 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.
Sema4, Sema4	RCV001011065	SCV002535947	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000814730	SCV002774638	uncertain significance	not provided	2024-10-24	criteria provided, single submitter	clinical testing	The MSH3 c.1366G>A (p.Glu456Lys) variant has been reported in the published literature in an individual with breast cancer (PMID: 33606809 (2021)). This variant has also been identified as a somatic variant in an individual with colorectal cancer (PMID: 31127692 (2019)). The frequency of this variant in the general population, 0.00012 (3/24942 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153855	SCV003843132	uncertain significance	Familial adenomatous polyposis 4	2022-10-26	criteria provided, single submitter	clinical testing	The MSH3 c.1366G>A (p.Glu456Lys) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with MSH3-associated polyposis syndrome. 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.
GeneDx	RCV000814730	SCV004022743	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31127692)
Baylor Genetics	RCV003461228	SCV004197113	uncertain significance	Endometrial carcinoma	2024-03-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751733	SCV005364275	uncertain significance	MSH3-related disorder	2024-05-09	no assertion criteria provided	clinical testing	The MSH3 c.1366G>A variant is predicted to result in the amino acid substitution p.Glu456Lys. This variant, along with missense variants in PMS1 and PMS2, has been reported in a tumor tissue sample from an individual with colorectal cancer; no additional studies were done to determine if the variants were germline or somatic (Supplementary Table 2, Chang YS et al 2019. PubMed ID: 31127692). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has been classified in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/658005/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.