ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.46G>A (p.Val16Met)

dbSNP: rs776643257
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214613 SCV000276667 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-15 criteria provided, single submitter clinical testing The p.V16M variant (also known as c.46G>A), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 46. The valine at codon 16 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000214613 SCV000537596 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000541506 SCV000625167 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-27 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 16 of the MLH1 protein (p.Val16Met). 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: 232514). 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 expected to disrupt MLH1 protein function with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV005031798 SCV005662490 uncertain significance Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2024-02-21 criteria provided, single submitter clinical testing

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