ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1622C>T (p.Thr541Ile) (rs864622079)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204365 SCV000259280 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 541 of the MSH2 protein (p.Thr541Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 219420). 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 tolerated, but 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.
GeneDx RCV000478447 SCV000566417 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1622C>T at the cDNA level, p.Thr541Ile (T541I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr541Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr541Ile occurs at a position that is not conserved and is located in the Clamp domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Thr541Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570070 SCV000669799 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000570070 SCV000903532 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing

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