Submissions for variant NM_000251.3(MSH2):c.1642G>T (p.Gly548Cys)

dbSNP: rs63750538

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524350	SCV000254389	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 548 of the MSH2 protein (p.Gly548Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16395668, 34250417). ClinVar contains an entry for this variant (Variation ID: 90714). 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 have shown that this missense change does not substantially affect MSH2 function (PMID: 30998989, 33357406). 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.
GeneDx	RCV000479671	SCV000565195	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with HNPCC (Auclair 206); Published functional studies demonstrate no damaging effect: variant classified as neutral based on a methylation tolerance assay (Bouvet 2019); This variant is associated with the following publications: (PMID: 16395668, 26333163, 18383312, 30998989)
Ambry Genetics	RCV000490983	SCV000580428	likely benign	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000490983	SCV001344570	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 548 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with Lynch syndrome (PMID: 16395668). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317077	SCV004020515	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1642G>T (p.Gly548Cys) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function, and the PON-MMR2 tool predicts a pathogenic effect (Niroula_2015). The variant was absent in 251216 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1642G>T has been reported in the literature in individuals affected with clinical features of Lynch Syndrome without strong evidence of causality (Auclair_2006, Pearlman_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least two publications report experimental evidence evaluating an impact on protein function, finding no MMR dysfunction in cells expressing the variant protein (Bouvet_2019, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 30998989, 16395668, 26333163, 34250417, 33357406). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003466965	SCV004193929	uncertain significance	Lynch syndrome 1	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997151	SCV004833993	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 548 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with Lynch syndrome (PMID: 16395668). This variant has not been identified 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.