ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1984A>T (p.Thr662Ser) (rs587778964)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000774205 SCV000907906 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing
Invitae RCV001036962 SCV001200353 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 662 of the MLH1 protein (p.Thr662Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). This variant disrupts the p.Thr662 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21404117, 11754112, 16341550, 20533529, 23403630, 17510385). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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