ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1480T>G (p.Cys494Gly)

dbSNP: rs876660952
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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 RCV000222327 SCV000278781 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-24 criteria provided, single submitter clinical testing The p.C494G variant (also known as c.1480T>G), located in coding exon 13 of the MLH1 gene, results from a T to G substitution at nucleotide position 1480. The cysteine at codon 494 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health RCV000222327 SCV001359144 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing This missense variant replaces cysteine with glycine at codon 494 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251480 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001325270 SCV001516255 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 494 of the MLH1 protein (p.Cys494Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 234240). 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.
Baylor Genetics RCV004567672 SCV005057985 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2024-02-09 criteria provided, single submitter clinical testing

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