Submissions for variant NM_000251.3(MSH2):c.149C>G (p.Ala50Gly)

dbSNP: rs876658582

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000470501	SCV000548149	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 50 of the MSH2 protein (p.Ala50Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408464). 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%. 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.
Ambry Genetics	RCV000561205	SCV000669746	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The p.A50G variant (also known as c.149C>G), located in coding exon 1 of the MSH2 gene, results from a C to G substitution at nucleotide position 149. The alanine at codon 50 is replaced by glycine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000662999	SCV000786000	uncertain significance	Lynch syndrome 1	2018-05-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561205	SCV001353151	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 50 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 not been reported in individuals affected with MSH2-related disorders in the literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284007	SCV001469552	uncertain significance	not provided	2020-08-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561205	SCV002528852	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	curation
GeneDx	RCV001284007	SCV002574561	uncertain significance	not provided	2022-03-15	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 21120944)
Myriad Genetics, Inc.	RCV000662999	SCV004018237	uncertain significance	Lynch syndrome 1	2023-03-16	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV004000777	SCV004831872	uncertain significance	Lynch syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 50 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 not been reported in individuals affected with MSH2-related disorders in the literature. 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.