ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1896+1G>T (rs267607867)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479456 SCV000568570 likely pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1896+1G>T or IVS16+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 16 of the MLH1 gene. This variant destroys a canonical splice donor 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 variant has been identified in several individuals suspected of having Lynch syndrome, including two whose tumors displayed microsatellite instability (MSI-H), with one also exhibiting loss of MLH1 protein expression on immunohistochemistry (IHC) (Nilbert 1999, Wahlberg 2002, Mangold 2005, Dymerska 2010, Bonadona 2011). Based on the currently available information, we consider MLH1 c.1896+1G>T to be a likely pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075405 SCV000106401 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrupts canonical donor splice site
Invitae RCV000684807 SCV000543560 pathogenic Hereditary nonpolyposis colon cancer 2018-06-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 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 observed in individuals affected with Lynch syndrome (PMID: 10533476, 15849733, 21642682). This variant is also described as a GAGgtg->GAGttg change in the splice donor site in the literature. ClinVar contains an entry for this variant (Variation ID: 89926). A different variant affecting this nucleotide (c.1896+1G>A) has been determined to be pathogenic (PMID: 12067992, Invitae). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.