ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1559-1G>C (rs267607837)

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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) RCV000075254 SCV000106252 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrupts canonical acceptor splice site
Invitae RCV000539690 SCV000625078 pathogenic Hereditary nonpolyposis colon cancer 2018-07-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals with suspected Lynch syndrome (PMID: 12624141, 15926618). This variant is also known as IVS13-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 89780). Different variants affecting this nucleotide (c.1559-1G>T, c.1559-1G>A) have been determined to be pathogenic (PMID: 8776590, 15849733). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

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