ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1546C>G (p.Gln516Glu)

dbSNP: rs1553653195
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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 RCV001012048 SCV001172448 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-26 criteria provided, single submitter clinical testing The p.Q516E variant (also known as c.1546C>G), located in coding exon 13 of the MLH1 gene, results from a C to G substitution at nucleotide position 1546. The glutamine at codon 516 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is poorly 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.
Invitae RCV003594069 SCV004368773 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 516 of the MLH1 protein (p.Gln516Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 819474). 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 MLH1 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.

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