ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2059del (p.Arg687fs) (rs863225381)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001067402 SCV001232463 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-20 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the MLH1 gene (p.Arg687Glyfs*96). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acids of the MLH1 protein and extend the protein by an additional 25 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 218022). While no functional studies have been performed to test the effect of this particular variant on MLH1 protein function or stability, it affects the highly conserved C-terminal domain (CTD) responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Different frameshift variants including c.2269dup, located downstream of this variant, have been determined to be pathogenic (PMID: 8128251, 9697702, 12810663, 14985405, Invitae). This suggests that disruption of this region of the MLH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202267 SCV000257083 likely pathogenic not provided no assertion criteria provided research

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.