ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.41C>T (p.Thr14Ile) (rs774363593)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456258 SCV000543527 uncertain significance Hereditary nonpolyposis colon cancer 2017-10-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 14 of the MLH1 protein (p.Thr14Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs774363593, ExAC 0.002%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 405381). 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: "Benign"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000478685 SCV000570081 uncertain significance not provided 2017-03-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.41C>T at the cDNA level, p.Thr14Ile (T14I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Thr14Ile was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr14Ile occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Thr14Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571643 SCV000669593 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)

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