ClinVar Miner

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

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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) RCV000075255 SCV000106253 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
GeneDx RCV000485205 SCV000565157 pathogenic not provided 2014-10-15 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.1559-1 G>T or IVS13-1 G>T and consists of a G>T nucleotide substitution at the -1 position of intron 13 of the MLH1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This mutation was identified in a family suspected of having Lynch syndrome (Nyström-Lahti 1996), and we consider it to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075255 SCV000592410 pathogenic Lynch syndrome 2016-03-23 criteria provided, single submitter clinical testing
Invitae RCV000799045 SCV000938692 pathogenic Hereditary nonpolyposis colon cancer 2019-11-06 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). Sequence variants affecting this splice acceptor have been observed in individuals with Lynch syndrome-associated tumors (PMID: 8776590, 10200055, 24344984, 12624141, 15926618, Invitae). ClinVar contains an entry for this variant (Variation ID: 89781). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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