Submissions for variant NM_000251.3(MSH2):c.1706A>G (p.Glu569Gly)

dbSNP: rs786201077

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162561	SCV000212972	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-17	criteria provided, single submitter	clinical testing	The p.E569G variant (also known as c.1706A>G), located in coding exon 11 of the MSH2 gene, results from an A to G substitution at nucleotide position 1706. The glutamic acid at codon 569 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168102	SCV000218758	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585899	SCV000696224	uncertain significance	not specified	2021-08-15	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1706A>G (p.Glu569Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250804 control chromosomes. 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.1706A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One database (UMD) reports its presence in an individual meeting the Amsterdam-II criteria with mismatch repair function in tumor cells reported as "MSS / MLH1+MSH2+MSH6+PMS2+ (in situ microcarcinoma part of polyp with low-grade dysplasia)". These reported findings do not support an actionable involvement of this variant in the etiology of disease. Five 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.
Counsyl	RCV000663034	SCV000786070	uncertain significance	Lynch syndrome 1	2018-02-15	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761166	SCV000891082	uncertain significance	Lynch syndrome	2020-10-14	criteria provided, single submitter	clinical testing	The MSH2 c.1706A>G (p.Glu569Gly) missense change has a maximum subpopulation frequency of 0.00088% in the gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47698148-A-G). In silico algorithms are not in agreement about a tolerated or damaging effect on the gene or protein product and functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. A different change at p.Glu569 has been reported in the literature in an individual with Lynch syndrome; this variant was observed in cis with a pathogenic variant in MSH2 c.1711G>T (p.Glu571*), indicating that the change at p.Glu569 may be benign. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting.
Color Diagnostics, LLC DBA Color Health	RCV000162561	SCV001734153	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 569 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250804 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.
Myriad Genetics, Inc.	RCV000663034	SCV004018681	likely benign	Lynch syndrome 1	2023-11-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV000663034	SCV004196218	uncertain significance	Lynch syndrome 1	2023-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV004777607	SCV005388996	uncertain significance	not provided	2024-03-04	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 suggest mismatch repair function comparable to wild-type (PMID: 33357406); This variant is associated with the following publications: (PMID: 27602174, 27363726, 18822302, 9774676, 21120944, 33357406)
All of Us Research Program, National Institutes of Health	RCV000761166	SCV005429124	uncertain significance	Lynch syndrome	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 569 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). 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 1/250804 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.