Submissions for variant NM_000179.3(MSH6):c.3356A>G (p.Glu1119Gly)

dbSNP: rs876661138

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000216765	SCV000279647	uncertain significance	not provided	2017-11-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3356A>G at the cDNA level, p.Glu1119Gly (E1119G) 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 Glu1119Gly was not observed 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 Glu1119Gly is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Glu1119Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000491795	SCV000580364	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-03	criteria provided, single submitter	clinical testing	The p.E1119G variant (also known as c.3356A>G), located in coding exon 5 of the MSH6 gene, results from an A to G substitution at nucleotide position 3356. The glutamic acid at codon 1119 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000536220	SCV000624850	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-14	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 234647). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1119 of the MSH6 protein (p.Glu1119Gly).
All of Us Research Program, National Institutes of Health	RCV003998636	SCV004839344	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1119 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 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.