Submissions for variant NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)

dbSNP: rs63750823

Total submissions: 9

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	2019-07-02	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region (Baehring 2006); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11754112, 15849733, 15926618, 24333619, 16736291, 26681312, 32710294)
Color Diagnostics, LLC DBA Color Health	RCV000772326	SCV000905464	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to deleteriously impact MLH1 function in two ways. The creation of the premature translation stop signal is expected to trigger nonsense-mediate decay, resulting in an absent product. Secondly, this variant has been shown to cause aberrant mRNA splicing, resulting in an in-frame deletion, r.66_116del (p.Glu23_Cys39del), in a conserved region of the ATPase domain (PMID: 16736291). The deleted region contains over a dozen pathogenic missense variant reports in ClinVar (variation ID: 17105, 89631, 89645, 89648, 89651, 89655, 90343, 90388, 90403, 619503, 561169, 823364, 955911), suggesting that this deletion may have functional impact. This variant has been observed in at least 5 individuals or families affected with colorectal cancer and/or Lynch syndrome (PMID: 15849733, 16736291, 25110875, 26681312) and is reported to segregate with disease in one pedigree that has colorectal cancer affected members across three generations (PMID: 16736291). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV000811317	SCV000951577	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-25	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. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 90331). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 11754112, 15849733, 16736291, 26681312). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258081	SCV001434923	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160551	SCV001450328	pathogenic	not provided	2016-11-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290676	SCV001478808	pathogenic	Hereditary nonpolyposis colon cancer	2021-01-27	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.67G>T (p.Glu23X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250858 control chromosomes (gnomAD and publication data). c.67G>T has been reported in the literature in individuals affected with colon cancer and HNPCC (Kruger_2001, Mangold_2005, Baehring_2006, Susswein_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. In addition, one expert panel (InSiGHT) classified this variant as pathogenic in 2013. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000772326	SCV002661846	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The p.E23* pathogenic mutation (also known as c.67G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 67. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration has been reported in a hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome family that satisfied Amsterdam I criteria (Krüger S et al. Hum. Mutat., 2002 Jan;19:82), as well as in additional families that satisfied either Amsterdam I/II criteria or Bethesda guidelines (Baehring J et al. Fam. Cancer, 2006;5:195-9; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). One study showed that this alteration also leads to aberrant splicing by the creation of a novel splice donor site within coding exon 1 of the MLH1 gene and identified an aberrant transcript via cDNA analysis that lacked 51 nucleotides of exon 1, leading to an in-frame deletion of 17 codons (Baehring J et al. Fam. Cancer, 2006;5:195-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation, an abnormal protein, or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV001258081	SCV004186427	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.