ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1732-?_(*193_?)del

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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) RCV000075339 SCV000106325 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Large deletion
University of Washington Department of Laboratory Medicine, University of Washington RCV000075339 SCV000266079 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000075339 SCV000563815 pathogenic Lynch syndrome 2016-11-29 criteria provided, single submitter clinical testing This variant is a gross deletion of the genomic region encompassing exons 16-19 of the MLH1 gene. The 5' boundary is likely confined to intron 16. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated MLH1 protein. Loss-of-function variants including gross deletions in MLH1 are known to be pathogenic. A similar deletion has been observed in 7 unrelated individuals affected with Lynch syndrome, colon cancer and/or sebaceous skin cancer (PMID: 14635101, 16143124, 15713769). This deletion is expected to remove the most C-terminal 179 amino acids (Glu578-Cys756) from the MLH1 protein. This region includes most of the PMS2 interaction domain, which is necessary for MLH1-PMS2 dimerization and normal protein functioning (PMID: 10037723, 11292842, 20533529). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202024 SCV000257061 pathogenic not provided no assertion criteria provided research

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