Submissions for variant NM_000251.3(MSH2):c.74G>A (p.Gly25Asp)

gnomAD frequency: 0.00003  dbSNP: rs767747378

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164134	SCV000214749	likely benign	Hereditary cancer-predisposing syndrome	2022-08-05	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	RCV000525136	SCV000625458	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164134	SCV000905801	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 25 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). This variant has been reported in an individual affected with ovarian carcinoma determined to be microsatellite stable but with indeterminate immunohistochemsitry results (PMID: 36230473). This variant has been identified in 4/250416 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193893	SCV001363052	uncertain significance	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.74G>A (p.Gly25Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-06 in 219022 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.74G>A in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001762365	SCV002000919	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with ovarian cancer and indeterminate mismatch repair immunohistochemistry (Yang et al., 2022); Published functional studies suggest no damaging effect: performed similar to wild type in an assay measuring resistance to 6-TG (Jia et al., 2020); This variant is associated with the following publications: (PMID: 23729658, 16929514, 36230473, 18822302, 21120944, 33357406)
Genetic Services Laboratory, University of Chicago	RCV001193893	SCV002072143	uncertain significance	not specified	2017-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462126	SCV004196316	uncertain significance	Lynch syndrome 1	2023-08-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995317	SCV004826327	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 25 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). This variant has been reported in an individual affected with ovarian carcinoma determined to be microsatellite stable but with indeterminate immunohistochemsitry results (PMID: 36230473). This variant has been identified in 4/250416 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.