ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1336G>A (p.Glu446Lys)

dbSNP: rs1669321230
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001203684 SCV001374858 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-10 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 446 of the MSH6 protein (p.Glu446Lys). 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: 935156). 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.
Ambry Genetics RCV002379769 SCV002692696 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-23 criteria provided, single submitter clinical testing The p.E446K variant (also known as c.1336G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1336. The glutamic acid at codon 446 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 RCV004010631 SCV004841284 uncertain significance Lynch syndrome 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 446 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.

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