ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.142C>G (p.Gln48Glu) (rs587778913)

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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 RCV000574574 SCV000662055 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-03 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence
Invitae RCV000805962 SCV000945938 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-14 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 48 of the MLH1 protein (p.Gln48Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. 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 disease. ClinVar contains an entry for this variant (Variation ID: 479672). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Gln48 amino acid residue in MLH1 have been observed in affected individuals (PMID: 19386570, 21404117, 24362816, 22395473). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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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