ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.551C>T (p.Ser184Leu)

dbSNP: rs1064796057
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481057 SCV000572449 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.551C>T at the cDNA level, p.Ser184Leu (S184L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser184Leu was not observed in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser184Leu occurs at a position that is not conserved and is located within the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ser184Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000798656 SCV000938282 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-06-04 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 184 of the MLH1 protein (p.Ser184Leu). 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: 422870). 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. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000481057 SCV002009356 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002350074 SCV002651119 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-20 criteria provided, single submitter clinical testing The p.S184L variant (also known as c.551C>T), located in coding exon 7 of the MLH1 gene, results from a C to T substitution at nucleotide position 551. The serine at codon 184 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not 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 RCV004003389 SCV004835298 uncertain significance Lynch syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 184 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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