ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2798C>T (p.Thr933Ile) (rs587779968)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588848 SCV000149431 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2798C>T at the cDNA level, p.Thr933Ile (T933I) 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 Thr933Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Thr933Ile is located in the helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Thr933Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000196057 SCV000254417 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 933 of the MSH2 protein (p.Thr933Ile). The threonine residue is weakly 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 been observed in an individual with colon cancer (Invitae). However, in that individual pathogenic alleles were also identified in MSH2, which suggests that this c.2798C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 127640). 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.
Ambry Genetics RCV000216013 SCV000278376 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000216013 SCV000537579 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588848 SCV000696257 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing Variant summary: c.2798C>T affects a non-conserved nucleotide, resulting in amino acid change from Thr to Ile. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is not found in 112106 control chromosomes. In addition, multiple clinical laboratories classified this variant as VUS. This variant was found in one individual in our laboratory who also carries heterozygous BRIP1 c.2392C>T(p.R798*, pathogenic). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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