ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1676T>C (p.Leu559Pro) (rs63750059)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000204126 SCV000259172 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
GeneDx RCV000522242 SCV000618313 likely pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1676T>C at the cDNA level, p.Leu559Pro (L559P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has been reported in an individual with MSI-H colon cancer from a family meeting Amsterdam II Lynch syndrome criteria (Hardt 2011). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) describes a family meeting Amsterdam I criteria and classifies this variant as likely pathogenic (Thompson 2014). MLH1 Leu559Pro was not observed in large population cohorts (Lek 2016). This variant is located in the regions of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MLH1 Leu559Pro to be a likely pathogenic variant.

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