ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2219T>C (p.Ile740Thr) (rs1044486319)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521049 SCV000616785 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2219T>C at the cDNA level, p.Ile740Thr (I740T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ile740Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ile740Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the PMS2/MLH3/PMS1 interaction region (Raevaara 2005, Kansikas 2011, 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 Ile740Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572122 SCV000664727 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000629754 SCV000750710 uncertain significance Hereditary nonpolyposis colon cancer 2017-08-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 740 of the MLH1 protein (p.Ile740Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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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