ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1896+2T>C
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.1896+2T>C
Variation ID: 89928 Accession: VCV000089928.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047685 (GRCh38) [ NCBI UCSC ] 3: 37089176 (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 Jun 21, 2019 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:37047684:T:C
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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 |
5529 | 5584 |
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
Help
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 (1) |
reviewed by expert panel
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Jun 21, 2019 | RCV000075407.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 3, 2021 | RCV001854293.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2022 | RCV002408584.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2022 | RCV003235032.1 |
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: SCV000106402.3
First in ClinVar: Dec 19, 2013 Last updated: Oct 01, 2019 |
Comment:
Interrupts canonical donor splice site
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Likely pathogenic
(Jul 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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Ambry Genetics
Accession: SCV002722540.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.1896+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 16 in the MLH1 gene. Alterations that disrupt the … (more)
The c.1896+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 16 in the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in multiple individuals with early-onset colon cancer, including a patient meeting Bethesda criteria whose tumor demonstrated high microsatellite instability and loss of MLH1 and PMS2 staining by immunohistochemistry (IHC) (Akiyama Y et al. Gastroenterology, 1997 Jan;112:33-9; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 13, 2022)
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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: SCV003933593.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more)
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25525159, 8978340, 15849733, 30256826, 34271781) (less)
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Pathogenic
(Oct 03, 2021)
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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: SCV002245783.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 89928). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 10533476, 12067992, 15849733, 21642682; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 16 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). (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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Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition. | Martin-Morales L | PloS one | 2018 | PMID: 30256826 |
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 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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 |
Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. | Wahlberg SS | Cancer research | 2002 | PMID: 12067992 |
Microsatellite instability is rare in rectal carcinomas and signifies hereditary cancer. | Nilbert M | European journal of cancer (Oxford, England : 1990) | 1999 | PMID: 10533476 |
Transforming growth factor beta type II receptor gene mutations in adenomas from hereditary nonpolyposis colorectal cancer. | Akiyama Y | Gastroenterology | 1997 | PMID: 8978340 |
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.1896+2T%3EC | - | - | - | - |
Text-mined citations for rs267607869 ...
HelpRecord last updated Feb 14, 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.