ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.59C>T (p.Ala20Val)

dbSNP: rs1391455682
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001177268 SCV001341444 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 20 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251402 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.
Genetic Services Laboratory, University of Chicago RCV001819880 SCV002067265 uncertain significance not specified 2019-02-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV001177268 SCV002656136 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-18 criteria provided, single submitter clinical testing The p.A20V variant (also known as c.59C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 59. The alanine at codon 20 is replaced by valine, an amino acid with 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003759003 SCV004518939 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 20 of the MLH1 protein (p.Ala20Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 919247). 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 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.

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