ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.3565A>C (p.Met1189Leu)

gnomAD frequency: 0.00004  dbSNP: rs557233869
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000805026 SCV000944968 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-03-14 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1189 of the MLH3 protein (p.Met1189Leu). This variant is present in population databases (rs557233869, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 649966). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV004028202 SCV002615581 uncertain significance not specified 2023-05-13 criteria provided, single submitter clinical testing The p.M1189L variant (also known as c.3565A>C), located in coding exon 4 of the MLH3 gene, results from an A to C substitution at nucleotide position 3565. The methionine at codon 1189 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well 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.

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