ClinVar Miner

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

dbSNP: rs1553412326
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Total submissions: 4
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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 2022-07-05 criteria provided, single submitter clinical testing The c.895A>G (p.K299E) alteration is located in exon 4 (coding exon 4) of the MSH6 gene. This alteration results from a A to G substitution at nucleotide position 895, causing the lysine (K) at amino acid position 299 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae 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.

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