ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.454-2A>G (rs267607753)

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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) RCV000075721 SCV000106732 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000218165 SCV000277157 pathogenic Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing The c.454-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the MLH1 gene. The functional significance of this splicing alteration has been investigated using patient RNA and was shown to result in exon 6 skipping (Auclair J et al. Hum. Mutat. 2006 Feb; 27(2):145-54). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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