ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1676T>G (p.Leu559Arg) (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) RCV000075310 SCV000106304 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation Variant reclassification: MLH1 methylation not tested in tumour
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001253790 SCV001429661 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-09 criteria provided, single submitter clinical testing Data used in classification: UK family 1: 4 cases of CRC over 2 generations (including 2 primaries in 1 individuals). 2 diagnosed age <40 years and 1 <50 years (PS4_sup). The variant is absent from gnomAD (PM2_mod). Predicted deleterious/damaging by in silico analysis. (SIFT prediction: deleterious, MutationTaster prediction: disease_causing, Polyphen2 HumVar prediction: probably damaging (PP3_sup). Functional evidence of disrupting binding of MLH1 with PMS2 in vitro (Belvederesi et al, 2006, PMID: 16724012) (PS3_mod). UK family 1: MSI high, BRAF normal and no MLH1 hypermethylation in one case and LOH of second MLH1 allele detected in another case (PP4_sup).

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