ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.64A>G (p.Lys22Glu)

dbSNP: rs1060502897
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000473092 SCV000551104 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-07-18 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 22 of the MSH6 protein (p.Lys22Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). ClinVar contains an entry for this variant (Variation ID: 410429). 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 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 RCV000582480 SCV000690465 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-08 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 22 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759152 SCV000888294 uncertain significance not provided 2018-06-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000582480 SCV001187512 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-19 criteria provided, single submitter clinical testing The p.K22E variant (also known as c.64A>G), located in coding exon 1 of the MSH6 gene, results from an A to G substitution at nucleotide position 64. The lysine at codon 22 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004001827 SCV004832310 uncertain significance Lynch syndrome 2024-04-16 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 22 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV004596200 SCV005090463 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing

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