Submissions for variant NM_000251.3(MSH2):c.2064G>A (p.Met688Ile)

gnomAD frequency: 0.00001  dbSNP: rs63750790

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165796	SCV000216543	benign	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000410248	SCV000267401	uncertain significance	Lynch syndrome 1	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000410248	SCV000488061	uncertain significance	Lynch syndrome 1	2015-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000524376	SCV000548225	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 688 of the MSH2 protein (p.Met688Ile). This variant is present in population databases (rs63750790, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9559627, 10777691, 14499697, 23741719, 30093976, 31386297, 31396961, 36135357). ClinVar contains an entry for this variant (Variation ID: 90875). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 17720936, 21309037, 22739024, 33357406). This variant disrupts the p.Met688 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10080150, 15075785, 20010080, 21225464, 21239990, 22739024). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV000165796	SCV000685006	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 688 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have demonstrated normal to intermediate impact in mismatch repair assays (PMID: 17720936, 21309037, 22739024, 26951660, 33357406) and normal interaction with MSH2, MSH6, and MLH1 (PMID: 21309037). This variant has been reported in individuals affected with colorectal, endometrial cancer (PMID: 9559627, 10777691, 14499697, 15365995), gastric cancer (PMID: 29050249), and esophageal cancer (PMID: 31396961) in the literature, but also in healthy individuals (PMID: 15527911). This variant has been identified in 8/251466 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.
Mendelics	RCV000410248	SCV001135750	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030713	SCV001193635	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000410248	SCV001300493	uncertain significance	Lynch syndrome 1	2017-06-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260344	SCV001437277	uncertain significance	not specified	2024-02-01	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2064G>A (p.Met688Ile) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 252024 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00057), allowing no conclusion about variant significance. c.2064G>A has been reported in the literature in multiple individuals/families affected with suspected Lynch Syndrome (examples- Yuan_1998, Nomura_2000, Banno_2003, Shin_2004), but has also been reported in unaffected controls (examples- Banno_2004, Olfson_2015). Two large case-control studies evaluating breast cancer genetic risk also reported this variant was not significantly enriched in the case cohorts (Dorling_2021, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (BRCA2 c.1813delA, p.Ile605Tyrfs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an intermediate mismatch-repair phenotype in a yeast-based assay (Gammie_2007), however most subsequent reports indicate no overall damaging effects of the variant on mismatch repair function and ability to interact with its binding partner MSH6 (examples- Wielders_2010, Martin-Lopez_2012, Houlleberghs_2016, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 14499697, 15527911, 30093976, 33471991, 17720936, 26951660, 33357406, 29050249, 31386297, 22739024, 10777691, 36243179, 26332594, 15365995, 21309037, 9559627, 23760103). ClinVar contains an entry for this variant (Variation ID: 90875). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001588898	SCV001817059	uncertain significance	not provided	2023-09-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: mixed results with respect to mismatch repair activity, protein stability, and binding ability (Gammie et al., 2007; Wielders et al., 2011; Martin-Lopez et al., 2012; Houlleberghs et al., 2016; Jia et al., 2020); Observed in individuals with colon cancer, gastric cancer, pancreatic, and other cancers, or hereditary non-polyposis colorectal cancer (HNPCC), as well as in healthy controls (Yuan et al., 1998; Nomura et al., 2000; Banno et al., 2004; Kim et al., 2017; Terashima et al., 2022; Scott et al., 2022; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 24933000, 22039344, 29050249, 22949387, 31386297, 22739024, 17720936, 21309037, 9559627, 26951660, 23760103, 26332594, 15365995, 10777691, 23741719, 15527911, 25871441, 30093976, 31396961, 32566746, 33357406, 34570441, 34328007, 26206375, 22179786, 15075785, 14499697, 36135357, 18822302, 21120944, 36550560, 37559881, 36243179)
CeGaT Center for Human Genetics Tuebingen	RCV001588898	SCV002496483	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410248	SCV004018367	uncertain significance	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000410248	SCV004196306	uncertain significance	Lynch syndrome 1	2023-08-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001588898	SCV004220974	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0021 (8/3814 chromosomes in Korean subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with polyps (PMID: 9559627 (1998)), colon cancer (PMID: 10777691 (2000), 23741719 (2013)), endometrial cancer (PMID: 14499697 (2003)), gastric cancer (PMID: 29050249 (2017)), breast cancer (PMID: 30093976 (2018), 33471991 (2021), 34570441 (2021)), and an unspecified cancer (PMID: 31386297 (2019)). Some of these individuals were suspected of hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 9559627 (1998), 10777691 (2000), 14499697 (2003)), and Lynch Syndrome (PMID: 31386297 (2019)). However, this variant has also been reported in unaffected individuals (PMID: 15527911 (2004), 26332594 (2015), 33471991 (2021)). Functional studies of this variant on the effect of MSH2 protein function were inconclusive ((PMID: 17720936 (2007), 21309037 (2011), 22739024 (2012), 26951660 (2016), 33357406 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997157	SCV004825272	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 688 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have demonstrated normal to intermediate impact in mismatch repair assays (PMID: 17720936, 21309037, 22739024, 26951660, 33357406) and normal interaction with MSH2, MSH6, and MLH1 (PMID: 21309037). This variant has been reported in individuals affected with colorectal, endometrial cancer (PMID: 9559627, 10777691, 14499697, 15365995), gastric cancer (PMID: 29050249), and esophageal cancer (PMID: 31396961) in the literature, but also in healthy individuals (PMID: 15527911). This variant has been identified in 8/251466 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.