ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.67del (p.Glu23fs)
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.67del (p.Glu23fs)
Variation ID: 90332 Accession: VCV000090332.18
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993610 (GRCh38) [ NCBI UCSC ] 3: 37035101 (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 28, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- E23fs
- Other names
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- Canonical SPDI
- NC_000003.12:36993609:GGGGG:GGGG
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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 | RCV000075823.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2023 | RCV000575040.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 23, 2021 | RCV001353400.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 6, 2022 | RCV000817865.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 5, 2019 | RCV001193211.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2023 | RCV003452762.1 |
Submissions - Germline
Classification
Help
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: SCV000106833.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variation introducing premature termination codon
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Pathogenic
(Aug 18, 2023)
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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: SCV000673815.5
First in ClinVar: Jan 01, 2018 Last updated: Oct 28, 2023 |
Comment:
The c.67delG pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 67, causing … (more)
The c.67delG pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 67, causing a translational frameshift with a predicted alternate stop codon (p.E23Kfs*13). This alteration was identified once in a Danish Lynch syndrome cohort (Nilbert M et al. Fam. Cancer, 2009 Jun;8:75-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361917.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MLH1 c.67delG (p.Glu23LysfsX13) 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.67delG (p.Glu23LysfsX13) 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. The variant was absent in 251404 control chromosomes (gnomAD). c.67delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (LS) or LS related cancers (e.g. Domingo _2004, Ferguson_2014, Dymerska_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. The variant has also been classified by an expert panel (InSiGHT) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002522532.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
PP4, PP5, PM2, PVS1
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Pathogenic
(May 06, 2022)
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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: SCV000958448.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu23Lysfs*13) 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.Glu23Lysfs*13) 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. ClinVar contains an entry for this variant (Variation ID: 90332). This variant is also known as c.63del and c.66delG. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15342696, 15713769, 16451135, 18566915, 19224586, 25081409). This variant is not present in population databases (gnomAD no frequency). (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: SCV004190059.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592329.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
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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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Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients. | Rashid MU | Hereditary cancer in clinical practice | 2019 | PMID: 31660093 |
Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing. | Ferguson SE | Cancer | 2014 | PMID: 25081409 |
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 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch syndrome and FAP patients. | Dymerska D | The Journal of molecular diagnostics : JMD | 2010 | PMID: 20007843 |
Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome. | Rouleau E | Human mutation | 2009 | PMID: 19224586 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression. | Mao G | Cell research | 2008 | PMID: 18227862 |
Some aspects of molecular diagnostics in Lynch syndrome. | Kurzawski G | Hereditary cancer in clinical practice | 2006 | PMID: 20223024 |
Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). | Kurzawski G | Clinical genetics | 2006 | PMID: 16451135 |
Spectrum of germ-line MLH1 and MSH2 mutations in Austrian patients with hereditary nonpolyposis colorectal cancer. | Wolf B | Wiener klinische Wochenschrift | 2005 | PMID: 15926618 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. | Domingo E | Journal of medical genetics | 2004 | PMID: 15342696 |
Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1. | Wahlberg S | Genetic testing | 1999 | PMID: 10495924 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.67del | - | - | - | - |
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Text-mined citations for rs63750822 ...
HelpRecord last updated Feb 28, 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.