ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2104-2A>G

dbSNP: rs267607889
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
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075539 SCV000106539 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Labcorp Genetics (formerly Invitae), Labcorp RCV001314807 SCV001505355 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-06-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colorectal or ovarian cancer (PMID: 8592341, 14635101, 15365995, 24362816). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90054). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 19 and introduces a new termination codon (PMID: 24362816). However the mRNA is not expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc. RCV003451105 SCV004185827 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-25 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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.