Submissions for variant NM_000251.2(MSH2):c.2648T>C (p.Ile883Thr) (rs1064796682)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478084	SCV000573642	uncertain significance	not provided	2017-02-23	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2648T>C at the cDNA level, p.Ile883Thr (I883T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile883Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile883Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the Helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile883Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000793156	SCV000932497	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2018-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 883 of the MSH2 protein (p.Ile883Thr). The isoleucine residue is highly 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 not been reported in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 423888). 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, 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.