ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.863C>T (p.Thr288Ile) (rs786203878)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167375 SCV000218228 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000213284 SCV000279858 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.863C>T at the cDNA level, p.Thr288Ile (T288I) 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 Thr288Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr288Ile occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is not located in a known functional domain (Pan 1997, Raevaara 2005, Hardt 2011). 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 Thr288Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000822528 SCV000963337 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 288 of the MLH1 protein (p.Thr288Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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. ClinVar contains an entry for this variant (Variation ID: 187629). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; 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.

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