Submissions for variant NM_000179.3(MSH6):c.3560A>G (p.Glu1187Gly)

gnomAD frequency: 0.00001  dbSNP: rs150632241

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464152	SCV000551220	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1187 of the MSH6 protein (p.Glu1187Gly). This variant is present in population databases (rs150632241, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 410492). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). 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.
GeneDx	RCV000486385	SCV000568927	uncertain significance	not provided	2017-11-27	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3560A>G at the cDNA level, p.Glu1187Gly (E1187G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu1187Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Glu1187Gly is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Glu1187Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000491973	SCV000580244	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-04	criteria provided, single submitter	clinical testing	The p.E1187G variant (also known as c.3560A>G), located in coding exon 7 of the MSH6 gene, results from an A to G substitution at nucleotide position 3560. The glutamic acid at codon 1187 is replaced by glycine, an amino acid with similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000491973	SCV000690375	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1187 of the MSH6 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 MSH6-related disorders in the literature. This variant has been identified in 3/250666 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.
PreventionGenetics, part of Exact Sciences	RCV004539952	SCV004771676	uncertain significance	MSH6-related disorder	2024-02-07	criteria provided, single submitter	clinical testing	The MSH6 c.3560A>G variant is predicted to result in the amino acid substitution p.Glu1187Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410492/). 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	RCV004001845	SCV004835093	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1187 of the MSH6 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 MSH6-related disorders in the literature. This variant has been identified in 3/250666 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.