ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1898T>C (p.Ile633Thr) (rs864622093)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206123 SCV000259316 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 633 of the MSH2 protein (p.Ile633Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 219446). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000519579 SCV000616939 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1898T>C at the cDNA level, p.Ile633Thr (I633T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in an HPV-positive head and neck squamous cell carcinoma (Lechner 2013). MSH2 Ile633Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile633Thr occurs at a position that is not conserved and is located within the ATPase domain and the region of interaction with EXO1 (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH2 Ile633Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562458 SCV000673870 likely benign Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000562458 SCV000690027 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing

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