ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2224C>T (p.Gln742Ter) (rs587778992)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075580 SCV000106578 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon within functional domain in last exon
Ambry Genetics RCV000574085 SCV000664836 pathogenic Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075580 SCV000914327 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Invitae RCV001040530 SCV001204110 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-03-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MLH1 gene (p.Gln742*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acids of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colon cancer (PMID: 21681552). ClinVar contains an entry for this variant (Variation ID: 90094). This variant disrupts the highly conserved C-terminal domain responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). A different truncating variant downstream of this variant (p.Lys751Serfs*3) has been reported in individuals affected with Lynch syndrome and has been determined to be pathogenic (PMID: 24802709, 8797773, 27295708, 18566915, 18931482). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. 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.