ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2063T>C (p.Met688Thr)

dbSNP: rs63749993
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000823002 SCV000963836 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 688 of the MSH2 protein (p.Met688Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 664827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. This variant disrupts the p.Met688 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10080150, 15075785, 20010080, 21225464, 21239990, 22739024). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV002415942 SCV002727640 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-14 criteria provided, single submitter clinical testing The p.M688T variant (also known as c.2063T>C), located in coding exon 13 of the MSH2 gene, results from a T to C substitution at nucleotide position 2063. The methionine at codon 688 is replaced by threonine, an amino acid with similar properties. Though this exact alteration has not been reported in the literature, another alteration at this same position, p.M688R, has been reported in multiple families with Lynch syndrome (Lin X et al. Dig. Dis. Sci. 1999 Mar; 44(3):553-9; Pastrello C et al. Genet. Med. 2011 Feb; 13(2):115-24). 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.
Baylor Genetics RCV003467514 SCV004194546 uncertain significance Lynch syndrome 1 2023-06-14 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002849 SCV004842785 uncertain significance Lynch syndrome 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 688 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2063T>G (p.Met688Arg), is considered to be disease-causing (ClinVar variation ID: 90874), suggesting that this position may be important for the protein function. 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.

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