Submissions for variant NM_000251.2(MSH2):c.1943T>A (p.Ile648Asn) (rs763100088)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222363	SCV000278504	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-10	criteria provided, single submitter	clinical testing	Insufficient evidence
GeneDx	RCV000523371	SCV000618299	uncertain significance	not provided	2017-03-12	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1943T>A at the cDNA level, p.Ile648Asn (I648N) at the protein level, and results in the change of an Isoleucine to an Asparagine (ATT>AAT). This variant has been reported in an individual with colon cancer reported to have microsatellite instability but normal immunohistochemistry (Poynter 2008). MSH2 Ile648Asn was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Isoleucine and Asparagine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile648Asn occurs at a position that is not conserved and is located in the ATPase domain and region of interaction with EXO1 (Lützen 2008). 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 Ile648Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000629936	SCV000750892	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with asparagine at codon 648 of the MSH2 protein (p.Ile648Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs763100088, ExAC 0.007%). This variant has been reported in a family affected with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 234021). 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.