Submissions for variant NM_000179.3(MSH6):c.2629G>A (p.Glu877Lys)

gnomAD frequency: 0.00001  dbSNP: rs730881797

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160682	SCV000211299	uncertain significance	not provided	2020-03-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533174	SCV000624780	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 877 of the MSH6 protein (p.Glu877Lys). This variant is not present in population databases (gnomAD no frequency). 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: 182636). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000580634	SCV000685303	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000986724	SCV001135822	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580634	SCV001177002	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	The p.E877K variant (also known as c.2629G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2629. The glutamic acid at codon 877 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160682	SCV002047901	uncertain significance	not provided	2020-12-21	criteria provided, single submitter	clinical testing	The MSH6 c.2629G>A; p.Glu877Lys variant (rs730881797), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 182636). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamate at codon 877 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.344). However, given the lack of clinical and functional data, the significance of the p.Glu877Lys variant is uncertain at this time.