Submissions for variant NM_000251.3(MSH2):c.2649T>G (p.Ile883Met)

gnomAD frequency: 0.00001  dbSNP: rs768983827

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580301	SCV000685068	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 883 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 25110875, 29442399), however, in one of these individuals this variant co-occurred with another potentially pathogenic MSH2 variant (PMID: 29442399). This variant has been identified in 3/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV000629841	SCV000750797	benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580301	SCV001177130	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-19	criteria provided, single submitter	clinical testing	The p.I883M variant (also known as c.2649T>G), located in coding exon 16 of the MSH2 gene, results from a T to G substitution at nucleotide position 2649. The isoleucine at codon 883 is replaced by methionine, an amino acid with highly similar properties. This alteration has been identified in an individual with an MSI-high colorectal cancer diagnosed at age 38 year and a metachronous endometrial cancer diagnosed at age 41 years showing loss of MSH2 on immunohistochemistry (Bae S et al. Korean J Obstet Gynecol 2012;55(11):870-873). This variant has also been identified in a large unselected colorectal cancer cohort (Sinn D et al. Hepatogastroenterology 2009;56(91-92):672-6), and in a cohort of 1135 Chinese patients with gastric cancer (Zhang C et al. J Med Genet, 2023 Aug;60:760-768). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193286	SCV001362020	uncertain significance	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2649T>G (p.Ile883Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276876 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2649T>G has been reported in the literature in an individual affected with Lynch Syndrome (Kang 2015, Lee 2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002245022	SCV002513688	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with MSH2-related cancers, including one individual with tumor studies consistent with pathogenic variants in this gene (Zhu 2013, Kang 2015, Lee 2018); This variant is associated with the following publications: (PMID: 19621678, 23760103, 27873144, 18822302, 9774676, 25110875, 29442399)
All of Us Research Program, National Institutes of Health	RCV004001259	SCV004826587	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 883 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 25110875, 29442399), however, in one of these individuals this variant co-occurred with another potentially pathogenic MSH2 variant (PMID: 29442399). This variant has been identified in 3/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.