ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1444G>A (p.Val482Met)

dbSNP: rs1057089565
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001181517 SCV001346675 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-21 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 482 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 not been reported in individuals affected with MLH1-related disorders in the literature. This variant has not been identified 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.
Invitae RCV001876030 SCV002164928 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 482 of the MLH1 protein (p.Val482Met). 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: 921860). 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.
Ambry Genetics RCV001181517 SCV002700247 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-24 criteria provided, single submitter clinical testing The p.V482M variant (also known as c.1444G>A), located in coding exon 13 of the MLH1 gene, results from a G to A substitution at nucleotide position 1444. The valine at codon 482 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other 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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