ClinVar Miner

Submissions for variant NM_001167617.2(MLH1):c.-450del (rs63750822)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075823 SCV000106833 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075823 SCV000592329 pathogenic Lynch syndrome 2013-01-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575040 SCV000673815 pathogenic Hereditary cancer-predisposing syndrome 2019-02-23 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion);Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000817865 SCV000958448 pathogenic Hereditary nonpolyposis colon cancer 2019-12-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu23Lysfs*13) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with clinical features of Lynch syndrome (PMID: 15342696, 25081409, 15713769, 18566915, 19224586, 16451135). This variant is also known as c.63del and c.66delG in the literature. ClinVar contains an entry for this variant (Variation ID: 90332). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193211 SCV001361917 pathogenic Lynch syndrome 2019-09-05 criteria provided, single submitter clinical testing Variant summary: MLH1 c.67delG (p.Glu23LysfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251404 control chromosomes (gnomAD). c.67delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (LS) or LS related cancers (e.g. Domingo _2004, Ferguson_2014, Dymerska_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. The variant has also been classified by an expert panel (InSiGHT) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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