ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)
Variation ID: 90331 Accession: VCV000090331.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993614 (GRCh38) [ NCBI UCSC ] 3: 37035105 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 Feb 14, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- E23*
- Other names
- p.E23*:GAA>TAA
- Canonical SPDI
- NC_000003.12:36993613:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5564 | 5619 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075822.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 2, 2019 | RCV000160551.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2021 | RCV000772326.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2023 | RCV000811317.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2023 | RCV001258081.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2021 | RCV001290676.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106835.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variation introducing premature termination codon & partial splicing aberration
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary non-polyposis colorectal cancer, type 2
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434923.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001478808.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002661846.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450328.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211129.11
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jul 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004186427.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(May 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000951577.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Oct 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000905464.2
First in ClinVar: May 20, 2019 Last updated: Jun 19, 2021 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. | Mensenkamp AR | Gastroenterology | 2014 | PMID: 24333619 |
A 'nonsense' mutation leads to aberrant splicing of hMLH1 in a German hereditary non-polyposis colorectal cancer family. | Baehring J | Familial cancer | 2006 | PMID: 16736291 |
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer. | Krüger S | Human mutation | 2002 | PMID: 11754112 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.67G%3ET | - | - | - | - |
Text-mined citations for rs63750823 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.