Submissions for variant NM_000251.3(MSH2):c.1505A>G (p.Asp502Gly)

gnomAD frequency: 0.00009  dbSNP: rs148192104

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115502	SCV000149411	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate mismatch repair activity similar to wildtype (Jia et al., 2020); Observed in individuals with uterine or prostate cancer (Yehia et al., 2018; Giri et al., 2022); This variant is associated with the following publications: (PMID: 22949387, 25921062, 9774676, 18822302, 21120944, 29684080, 36243179, 35666082, 33357406)
Ambry Genetics	RCV000222010	SCV000275223	likely benign	Hereditary cancer-predisposing syndrome	2023-05-10	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	RCV000475133	SCV000548270	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222010	SCV000905148	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 502 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 uterine cancer (PMID: 29684080). This variant has been identified in 3/246126 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	RCV001527007	SCV001737818	uncertain significance	not specified	2023-07-05	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1505A>G (p.Asp502Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) 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 0.00024 in 326372 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00024 vs 0.00057), allowing no conclusion about variant significance. c.1505A>G has been reported in the literature in a individual affected with prostate cancer as well as in unaffected controls (Giri_2022, Okawa_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36243179, 35666082). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000222010	SCV002534376	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	curation
Baylor Genetics	RCV003460819	SCV004196283	uncertain significance	Lynch syndrome 1	2023-08-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115502	SCV004220950	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (4/24868 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with uterine cancer (PMID: 29684080 (2018)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004529930	SCV004732851	uncertain significance	MSH2-related disorder	2024-01-23	criteria provided, single submitter	clinical testing	The MSH2 c.1505A>G variant is predicted to result in the amino acid substitution p.Asp502Gly. This variant has not been reported in the literature in individuals with MSH2 related disease. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127630/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997270	SCV004833474	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 502 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 uterine cancer (PMID: 29684080). This variant has been identified in 3/246126 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.