ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2141G>A (p.Trp714Ter) (rs63751022)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075553 SCV000106549 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon with functional domain
Ambry Genetics RCV000165669 SCV000216407 pathogenic Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000075553 SCV000696149 pathogenic Lynch syndrome 2016-07-06 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2141G>A (p.Trp714X) variant results in a premature termination codon, predicted to cause a truncation of C-terminal domain, a known mechanisms for disease. The functional studies demonstrated that hMLH1-hMRE11 interaction was dramatically decreased by p.Trp714X, and truncated protein lacks MMR activity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2179_2182delCACA/p.His727fsX55). This variant has been reported in numerous Lynch Syndrome patients and is absent in 121240 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV001044497 SCV001208298 pathogenic Hereditary nonpolyposis colon cancer 2019-05-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MLH1 gene (p.Trp714*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acids of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 30256826, 8863153) and has been reported to segregate with disease in a family (PMID: 8863153). ClinVar contains an entry for this variant (Variation ID: 90068). This variant has been reported to affect MLH1 protein function (PMID: 9697702, 17510385, 12810663). This truncation affects the highly conserved C-terminal domain responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Different truncating variants downstream of this variant (including p.Lys732* and p.Tyr750*) have been reported in individuals affected with Lynch syndrome and have been determined to be pathogenic (PMID: 10923051, 25197397, 10422993, 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.
Pathway Genomics RCV000144606 SCV000189933 pathogenic Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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