ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2651T>C (p.Ile884Thr) (rs63750409)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485019 SCV000565978 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2651T>C at the cDNA level, p.Ile884Thr (I884T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has been observed in at least one individual with colon cancer (Kim 2010). MSH2 Ile884Thr was not observed in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile884Thr is located within the Helix-turn-helix domain and a region that interacts with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether MSH2 Ile884Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000549838 SCV000625401 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 884 of the MSH2 protein (p.Ile884Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21034533). ClinVar contains an entry for this variant (Variation ID: 418714). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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