ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1731+1G>C (rs267607853)

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) RCV000075323 SCV000106317 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrupts canonical donor splice site
Invitae RCV000693129 SCV000820985 likely pathogenic Hereditary nonpolyposis colon cancer 2018-06-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 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 several families affected with Lynch syndrome (PMID: 16034045, 11208710, 20587412). This variant is also known as IVS15+1 G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 89849). 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). 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000075323 SCV000887324 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1731+1G>C has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

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.