Submissions for variant NM_000179.2(MSH6):c.3356A>G (p.Glu1119Gly) (rs876661138)

Total submissions: 3

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	2016-07-07	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
Invitae	RCV000536220	SCV000624850	uncertain significance	Hereditary nonpolyposis colon cancer	2017-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with glycine at codon 1119 of the MSH6 protein (p.Glu1119Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234647). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.