ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1675C>A (p.Leu559Met) (rs780221881)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486408 SCV000565160 uncertain significance not provided 2015-09-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1675C>A at the cDNA level, p.Leu559Met (L559M) 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 Leu559Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Leu559Met occurs at a position that is conserved across species, with Methionine being the naturally occurring amino acid in one species, and is located in the PMS2/MLH3/PMS1/EXO1 interaction domain (Raevaara 2005, Tournier 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Leu559Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565526 SCV000669549 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000565526 SCV000684765 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing

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