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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