ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1538T>C (p.Ile513Thr) (rs876658689)

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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 RCV000220692 SCV000274281 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000219458 SCV000279891 uncertain significance not provided 2016-02-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1538T>C at the cDNA level, p.Ile513Thr (I513T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ile513Thr 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 Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ile513Thr occurs at a position that is conserved across species and is located in the region of interaction with PMS2, MLH3, PMS1, and EXO1 (Raevaara 2005, UniProt). 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 Ile513Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220692 SCV000905844 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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