ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1761G>A (p.Met587Ile)

gnomAD frequency: 0.00001  dbSNP: rs747665234
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001058153 SCV001222700 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 587 of the MLH1 protein (p.Met587Ile). This variant is present in population databases (rs747665234, gnomAD 0.007%). This missense change has been observed in individual(s) with MLH1-related conditions (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 853362). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics RCV002402421 SCV002711738 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-16 criteria provided, single submitter clinical testing The p.M587I variant (also known as c.1761G>A), located in coding exon 16 of the MLH1 gene, results from a G to A substitution at nucleotide position 1761. The methionine at codon 587 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003462572 SCV004195101 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-09-21 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000100 SCV004843209 uncertain significance Lynch syndrome 2024-06-11 criteria provided, single submitter clinical testing This missense variant replaces methionine with isoleucine at codon 587 of the MLH1 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 and/or polyps undergoing screening for Lynch Syndrome (PMID: 25980754). This variant has been identified in 1/251248 chromosomes 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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