Submissions for variant NM_000251.3(MSH2):c.2054T>G (p.Ile685Arg)

dbSNP: rs1667303602

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001983983	SCV002279499	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-04-14	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant affects MSH2 protein function (PMID: 33357406). This sequence change replaces isoleucine with arginine at codon 685 of the MSH2 protein (p.Ile685Arg). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Lynch syndrome (Invitae, external communication). It has also been observed to segregate with disease in related individuals. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002423208	SCV002725551	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	clinical testing	The p.I685R pathogenic variant (also known as c.2054T>G), located in coding exon 13 of the MSH2 gene, results from a T to G substitution at nucleotide position 2054. The isoleucine at codon 685 is replaced by arginine, an amino acid with similar properties. This variant was identified in a proband whose family history met Amsterdam II criteria for Lynch syndrome and one relative who also tested positive for this variant had a colorectal tumor that demonstrated loss of both MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). Based on an internal structural analysis using published crystal structures, p.I685R is more disruptive to the region near the ATP-binding site than nearby pathogenic variants (Ambry internal data; Warren JJ et al. Mol Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003453939	SCV004186607	likely pathogenic	Lynch syndrome 1	2023-08-07	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data].