ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.67G>T (p.Glu23Ter) (rs63750823)

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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) RCV000075822 SCV000106835 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon & partial splicing aberration
GeneDx RCV000160551 SCV000211129 pathogenic not provided 2018-12-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.67G>T at the cDNA level and p.Glu23Ter (E23X) at the protein level. This is a nonsense variant, changing a Glutamic Acid to a premature stop codon. An RT-PCR assay showed two transcripts, the wild-type and an in-frame deletion of the last 17 residues of exon 1, but failed to identify a transcript with the premature stop codon suggesting that the mechanism of this variant is primarily aberrant splicing due to the creation of a de novo splice donor site (Baehring 2006). In addition, the loss of these 17 amino acids would remove part of the ATP-binding domain (Raevaara 2005). This variant has been observed in several individuals with colorectal cancer and family histories meeting Bethesda guidelines and/or Amsterdam criteria for Lynch syndrome (Kruger 2001, Mangold 2005, Wolf 2005, Baehring 2006). Tumor testing results in several of these individuals revealed microsatellite instability (MSI-H) as well as absence of MLH1 protein expression on tumor immunohistochemistry (Kruger 2002, Baehring 2006). Furthermore, MLH1 c.67G>T was shown to segregate with Lynch syndrome-associated cancers in one family (Baehring 2006). Lastly, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Color RCV000772326 SCV000905464 pathogenic Hereditary cancer-predisposing syndrome 2017-02-13 criteria provided, single submitter clinical testing
Invitae RCV000811317 SCV000951577 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu23*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome in a single family (PMID: 16736291), and identified in individuals affected with Lynch syndrome or suspected Lynch syndrome (PMID: 11754112, 15849733, 26681312). ClinVar contains an entry for this variant (Variation ID: 90331). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258081 SCV001434923 pathogenic Lynch syndrome II 2019-02-01 criteria provided, single submitter clinical testing This c.67G>T (p.Glu23*) variant in the MLH1 gene was predicted to result in an early stop codon, however, RT-PCR analysis indicates that the nucleotide change creates a new consensus donor splice site which results in the deletion of the last 51 nucleotides/17 residues of exon 1, rather than an early termination codon (PMID 16736291). Thus, this variant causes a splicing defect rather than early truncation of the protein. The deleted portion of exon 1 comprises an essential portion of the ATPase domain and thus is predicted to be a loss of function mutation, which is known to be a disease-causing mechanism for colorectal cancer. This variant has been reported in multiple unrelated families with colorectal cancer that fulfill Amsterdam I or II criteria, or have diagnoses of Lynch Syndrome (PMID 16736291, 11754112, 15849733 and 24333619). The tumors analyzed from patients with this variant have lost immunohistochemical staining for MLH1 and have been MSI-high. This variant is not been observed in the general population databases. Therefore, the c.67G>T (p.Glu23*) variant in the MLH1 gene is classified as pathogenic.

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