Submissions for variant NM_000179.3(MSH6):c.895A>G (p.Lys299Glu)

dbSNP: rs1553412326

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603999	SCV000712777	uncertain significance	not specified	2017-01-11	criteria provided, single submitter	clinical testing	The p.Lys299Glu variant in MSH6 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Lys299Glu variant is uncertain.
Ambry Genetics	RCV002448845	SCV002682094	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-15	criteria provided, single submitter	clinical testing	The p.K299E variant (also known as c.895A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 895. The lysine at codon 299 is replaced by glutamic acid, 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529344	SCV003027863	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-25	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. ClinVar contains an entry for this variant (Variation ID: 505514). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 299 of the MSH6 protein (p.Lys299Glu).
All of Us Research Program, National Institutes of Health	RCV004002483	SCV004825785	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 299 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer or colon polys (PMID: 31422818) and an individual affected with prostate cancer (PMID: 32832836). 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.