ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2237T>C (p.Leu746Pro)

dbSNP: rs2085649541
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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 RCV001176188 SCV001340069 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-04 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 746 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). 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 RCV001875801 SCV002245222 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-07-30 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 expected to disrupt MLH1 protein function. This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 918533). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 746 of the MLH1 protein (p.Leu746Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.
Ambry Genetics RCV001176188 SCV002725453 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-27 criteria provided, single submitter clinical testing The p.L746P variant (also known as c.2237T>C), located in coding exon 19 of the MLH1 gene, results from a T to C substitution at nucleotide position 2237. The leucine at codon 746 is replaced by proline, 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.

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