ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.422T>C (p.Met141Thr) (rs768313658)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759834 SCV000566957 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.422T>C at the cDNA level, p.Met141Thr (M141T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Met141Thr was observed at an allele frequency of 0.01% (2/17248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Met141Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759834 SCV000889439 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing
Color RCV000773079 SCV000906513 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
Invitae RCV001246708 SCV001420084 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 141 of the MSH2 protein (p.Met141Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs768313658, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419266). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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