ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2221C>A (p.Leu741Met) (rs786203583)

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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 RCV000166962 SCV000217783 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000215072 SCV000279864 uncertain significance not provided 2016-02-05 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2221C>A at the cDNA level, p.Leu741Met (L741M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu741Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu741Met occurs at a position that is conserved across species and is located within the Pms1p-interactive domain as well as the region of interaction with PMS2, MLH3, and PMS1 (Pang 1997, Raevaara 2005). 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 Leu741Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000560309 SCV000625135 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 741 of the MLH1 protein (p.Leu741Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 187247). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000166962 SCV000689868 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing

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