ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.24T>G (p.Ile8Met)

dbSNP: rs748406142
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001061739 SCV001226492 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-07-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 8 of the MLH1 protein (p.Ile8Met). 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: 856302). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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 RCV002429695 SCV002742332 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-28 criteria provided, single submitter clinical testing The p.I8M variant (also known as c.24T>G), located in coding exon 1 of the MLH1 gene, results from a T to G substitution at nucleotide position 24. The isoleucine at codon 8 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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