Submissions for variant NM_000251.3(MSH2):c.742A>G (p.Lys248Glu)

gnomAD frequency: 0.00001  dbSNP: rs587779178

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235646	SCV000292935	uncertain significance	not provided	2019-04-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22949387, 22290698, 18383312, 16995940, 26333163, 26951660, 14526391)
Ambry Genetics	RCV000491084	SCV000580531	likely benign	Hereditary cancer-predisposing syndrome	2022-09-29	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.
Invitae	RCV000630103	SCV000751059	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491084	SCV002534559	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265598	SCV002547922	uncertain significance	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.742A>G (p.Lys248Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251368 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although reported in the literature (example, Lastella_2006), to our knowledge, no case level occurrence of c.742A>G in individuals affected with Lynch Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect although reporting a consensus classification of neutral (example, Jia_2021). Therefore, this study is not weighted as a directly traceable evidence in the context of this evaluation. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003389041	SCV004194501	uncertain significance	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491084	SCV004356627	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 248 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 5/251368 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.
All of Us Research Program, National Institutes of Health	RCV003997180	SCV004821672	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 248 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 5/251368 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003389041	SCV004101130	uncertain significance	Lynch syndrome 1	2023-11-02	no assertion criteria provided	clinical testing