Submissions for variant NM_000251.3(MSH2):c.593A>G (p.Glu198Gly)

dbSNP: rs63750327

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076649	SCV000107684	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Mendelics	RCV000986651	SCV001135705	benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001524492	SCV001734361	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 198 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). This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). Another study demonstrated that this variant is resistant to methylation-inducted cell death and likely defective in mismatch-repair (PMID: 30998989). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12702580), and it has been described that this variant segregates with disease (PMID: 12702580). However, multiple tumors show microsatellite stability (PMID: 17312306). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV002465508	SCV002760190	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-10-08	criteria provided, single submitter	curation	Data included in classification: Revel: 0.99 (PP3_sup) Absent from 118479 gnomAD v.2.1.1 non-cancer WES samples (PM2_mod) Jia et al., 2021, PMID: 33357406 – loss of function Bouvet (2019) PMID: 30998989: loss of function on methylation assay Protein expression/stability dramatically affected in yeast, 4% of WT Gammie et al., 2007, PMID: 17720936 Abolished interactions with MSH6, MSH3, MLH1, PMS1, EXO1 and POL30 in yeast two-hybrid assay proficient on yeast assay Martinez & Kolodner, 2010 PMID: 20176959 – 1.8% deficiency in Thr+ reversion assay, 0.2% deficiency in Lys+ assay & no significant change in Canr mutator assay (PS3_Str) Data not included in classification: 17 observations in LOVD Not seen in 2841 UK diagnostic tests No other clinically classified variants at codon. 4/6 missense variants at codon deleterious on Jia et al., 2021 assay
All of Us Research Program, National Institutes of Health	RCV000076649	SCV004830761	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 198 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). This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). Another study demonstrated that this variant is resistant to methylation-inducted cell death and likely defective in mismatch-repair (PMID: 30998989). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12702580), and it has been described that this variant segregates with disease (PMID: 12702580). However, multiple tumors show microsatellite stability (PMID: 17312306). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.