Submissions for variant NM_000251.3(MSH2):c.2141C>T (p.Ala714Val)

gnomAD frequency: 0.00001  dbSNP: rs63751224

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535935	SCV000625355	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-09-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574384	SCV000662221	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-23	criteria provided, single submitter	clinical testing	The p.A714V variant (also known as c.2141C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2141. The alanine at codon 714 is replaced by valine, an amino acid with similar properties. This alteration has been detected in 1 Korean HNPCC kindred and was absent from 300 healthy Korean individuals (Kim JC et al, Fam. Cancer 2004; 3(2):129-37). Functional analyses of this variant in yeast have demonstrated protein interaction, function, and expression comparable to wild type MSH2 (Gammie AE et al, Genetics 2007 Oct; 177(2):707-21). A study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 11;40:2044-2056). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). 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.
Color Diagnostics, LLC DBA Color Health	RCV000574384	SCV001344425	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 714 of the MSH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 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	RCV003997159	SCV004825681	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 714 of the MSH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 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.
PreventionGenetics, part of Exact Sciences	RCV004537294	SCV004734289	uncertain significance	MSH2-related disorder	2023-11-06	no assertion criteria provided	clinical testing	The MSH2 c.2141C>T variant is predicted to result in the amino acid substitution p.Ala714Val. This variant was reported in an individual with colorectal cancer (Table 1, Kim et al. 2004. PubMed ID: 15340264; Table 1, Zhu et al. 2013. PubMed ID: 23760103). Experimental studies suggest this variant does not impact protein mismatch repair activity (Table 2, referred to as msh2-A733V, Gammie et al. 2007. PubMed ID: 17720936; Figure 3, Rath et al. 2019. PubMed ID: 31237724; Tables S4 and S5, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 1 of ~31,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/2-47703641-C-T?dataset=gnomad_r2_1). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/90907/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.