ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2248A>C (p.Thr750Pro)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV003182646 SCV003867471 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-20 criteria provided, single submitter clinical testing The p.T750P variant (also known as c.2248A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2248. The threonine at codon 750 is replaced by proline, an amino acid with highly similar properties. This variant was identified in an individual with a pathogenic MLH1 mutation whose tumor showed loss of MLH1 by immunohistochemistry analysis; MSH6 staining was present (Okkels H et al. Appl Immunohistochem Mol Morphol, 2012 Oct;20:470-7).This amino acid position is well 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 RCV004009649 SCV004842054 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 750 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 who was reported to also carry a pathogenic variant in the MLH1 gene (PMID: 22495361). The tumor showed normal protein expression of MSH6 protein. 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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