ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2194A>T (p.Lys732Ter) (rs267607906)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075573 SCV000106570 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon within functional domain in last exon
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075573 SCV000592445 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Invitae RCV000558933 SCV000625133 pathogenic Hereditary nonpolyposis colon cancer 2017-10-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the MLH1 mRNA at codon 732 (p.Lys732*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 25 amino acids of the MLH1 protein. Loss-of-function variants in MLH1 are known to be pathogenic. This particular variant has been reported in the literature in an individual with Lynch syndrome (PMID: 10923051) and an individual with Muir-Torre syndrome (PMID: 25197397). This truncation affects the highly conserved C-terminal domain (CTD) responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Different truncations downstream of this variant (p.Tyr750*, p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 24802709, 8797773, 27295708, 18566915, 18931482 and Invitae database). This suggests that deletion of this region of the MLH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000564805 SCV000676048 pathogenic Hereditary cancer-predisposing syndrome 2017-08-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation

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