ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.404T>C (p.Leu135Pro)

dbSNP: rs753233578
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222713 SCV000279540 uncertain significance not provided 2022-08-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075)
Invitae RCV001206786 SCV001378113 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-04-09 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 234592). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 135 of the MLH1 protein (p.Leu135Pro).
Ambry Genetics RCV003278705 SCV004006417 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-16 criteria provided, single submitter clinical testing The p.L135P variant (also known as c.404T>C), located in coding exon 5 of the MLH1 gene, results from a T to C substitution at nucleotide position 404. The leucine at codon 135 is replaced by proline, an amino acid with similar properties. This amino acid position is well 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.
All of Us Research Program, National Institutes of Health RCV003998633 SCV004838334 uncertain significance Lynch syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 135 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.

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