ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1668-1G>A
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.1668-1G>A
Variation ID: 89826 Accession: VCV000089826.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37042267 (GRCh38) [ NCBI UCSC ] 3: 37083758 (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 Jun 21, 2019 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:37042266:G:A
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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 |
5531 | 5586 |
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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Likely pathogenic (3) |
reviewed by expert panel
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Jun 21, 2019 | RCV000075300.11 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2022 | RCV000214110.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV000629693.6 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001353428.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2023 | RCV003451048.1 |
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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Likely pathogenic
(Jun 21, 2019)
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reviewed by expert panel
Method: curation
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106296.3
First in ClinVar: Dec 19, 2013 Last updated: Oct 01, 2019 |
Comment:
Interrupts canonical donor splice site
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Likely pathogenic
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266075.2
First in ClinVar: Mar 24, 2015 Last updated: Apr 09, 2018 |
Comment:
MLH1 NM_000249.3:c.1668-1G>A was observed in one family with several cases of early-onset colon and endometrial cancer (Shirts et al 2016, PMID 26845104). It was also … (more)
MLH1 NM_000249.3:c.1668-1G>A was observed in one family with several cases of early-onset colon and endometrial cancer (Shirts et al 2016, PMID 26845104). It was also seen as an apparent passenger mutation in a tumor with other somatic mutations apparently responsible for the observed MSI status, reducing the likelihood of pathogenicity (Shirts et al 2018, PMID 29887214). This has been reported as likely pathogenic by the InSiGHT consortium and as pathogenic by several laboratories. We currently consider this variant to be likely pathogenic. (less)
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Likely pathogenic
(Jan 26, 2018)
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criteria provided, single submitter
Method: research
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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Academic Department of Medical Genetics, University of Cambridge
Accession: SCV000992193.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
Comment:
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Clinical Features:
Sarcoma (present) , Adenocarcinoma of the large intestine (present)
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Pathogenic
(Apr 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731290.2
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Comment:
The c.1668-1G>A variant in MLH1 has been reported in at least 4 individuals with Lynch Syndrome (Lamberti 2006, Arnold 2009, Pérez-Carbonell 2012, Shirts 2016) and … (more)
The c.1668-1G>A variant in MLH1 has been reported in at least 4 individuals with Lynch Syndrome (Lamberti 2006, Arnold 2009, Pérez-Carbonell 2012, Shirts 2016) and was found to segregate with disease in 2 additional affected individuals in one family (Arnold 2009). This variant was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been observed to cause altered splicing leading to an abnormal or absent protein (Arnold 2009, Pérez-Carbonell 2012). Heterozygous loss of function of the MLH1 gene is an established disease mechanism in Lynch Syndrome. Additionally, this variant has been classified as Likely pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT panel (ClinVar SCV000106296.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner. ACMG/AMP criteria applied: PM2, PS4_Supporting, PVS1. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 19, 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: SCV000278026.7
First in ClinVar: May 29, 2016 Last updated: Apr 15, 2023 |
Comment:
The c.1668-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 15 of the MLH1 gene. This alteration … (more)
The c.1668-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 15 of the MLH1 gene. This alteration has been previously reported in several individuals with colorectal cancers demonstrating microsatellite instability and absent MLH1 and/or PMS2 IHC staining, including individuals meeting Amsterdam criteria (Taylor CF, et al. Hum. Mutat. 2003 Dec; 22(6):428-33; Piñol V, et al. JAMA 2005 Apr; 293(16):1986-94; Lamberti C, et al. Digestion 2006 ; 74(1):58-67; Pérez-Carbonell L, et al. Gut 2012 Jun; 61(6):865-72; Walker M et al. Br J Surg, 2007 Dec;94:1567-71). One splicing assay using cell lines from mutation carriers found that this alteration results in out-of-frame skipping of exon 15 (Arnold S, et al. Hum. Mutat. 2009 May; 30(5):757-70). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Jul 21, 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: SCV004186354.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an … (more)
This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. (less)
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Pathogenic
(Jan 01, 2022)
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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: SCV000684764.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 14 of the MLH1 gene. Functional RNA studies have shown … (more)
This variant causes a G to A nucleotide substitution at the -1 position of intron 14 of the MLH1 gene. Functional RNA studies have shown that this variant causes out-of-frame deletion of exon 15 (PMID: 2707453). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer with tumors showing microsatellite instability and loss of MLH1 protein expression (PMID: 2707453, 15855432, 17095871, 19267393, 21868491). 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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Pathogenic
(Mar 14, 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: SCV000750649.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 89826). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 14635101, … (more)
ClinVar contains an entry for this variant (Variation ID: 89826). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 14635101, 15855432, 17095871, 19267393, 21868491). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in exon skipping and introduces a premature termination codon (PMID: 19267393). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV000592416.2 First in ClinVar: Mar 24, 2015 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 1
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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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Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes. | Tian W | International journal of cancer | 2019 | PMID: 31054147 |
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. | Sunga AY | Cancer genetics | 2017 | PMID: 28449805 |
Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. | Morris B | BMC genetics | 2016 | PMID: 27363726 |
Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer. | Pérez-Carbonell L | Gut | 2012 | PMID: 21868491 |
Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. | Arnold S | Human mutation | 2009 | PMID: 19267393 |
Selecting patients with young-onset colorectal cancer for mismatch repair gene analysis. | Walker M | The British journal of surgery | 2007 | PMID: 17665423 |
Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany. | Lamberti C | Digestion | 2006 | PMID: 17095871 |
Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. | Piñol V | JAMA | 2005 | PMID: 15855432 |
Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. | Taylor CF | Human mutation | 2003 | PMID: 14635101 |
Severe ovarian hyperstimulation syndrome: a reevaluated therapeutic approach. | Borenstein R | Fertility and sterility | 1989 | PMID: 2707453 |
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.1668-1G%3EA | - | - | - | - |
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Text-mined citations for rs267607845 ...
HelpRecord last updated Mar 05, 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.