ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1890dup (p.Asp631Ter)
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.1890dup (p.Asp631Ter)
Variation ID: 185190 Accession: VCV000185190.12
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047675-37047676 (GRCh38) [ NCBI UCSC ] 3: 37089166-37089167 (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 Feb 19, 2018 Feb 14, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1890dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Asp631Ter nonsense NM_000249.3:c.1890dupT NM_001167617.3:c.1596dup NP_001161089.1:p.Asp533Ter nonsense NM_001167618.3:c.1167dup NP_001161090.1:p.Asp390Ter nonsense NM_001167619.3:c.1167dup NP_001161091.1:p.Asp390Ter nonsense NM_001258271.2:c.1890dup NP_001245200.1:p.Asp631Ter nonsense NM_001258273.2:c.1167dup NP_001245202.1:p.Asp390Ter nonsense NM_001258274.3:c.1167dup NP_001245203.1:p.Asp390Ter nonsense NM_001354615.2:c.1167dup NP_001341544.1:p.Asp390Ter nonsense NM_001354616.2:c.1167dup NP_001341545.1:p.Asp390Ter nonsense NM_001354617.2:c.1167dup NP_001341546.1:p.Asp390Ter nonsense NM_001354618.2:c.1167dup NP_001341547.1:p.Asp390Ter nonsense NM_001354619.2:c.1167dup NP_001341548.1:p.Asp390Ter nonsense NM_001354620.2:c.1596dup NP_001341549.1:p.Asp533Ter nonsense NM_001354621.2:c.867dup NP_001341550.1:p.Asp290Ter nonsense NM_001354622.2:c.867dup NP_001341551.1:p.Asp290Ter nonsense NM_001354623.2:c.867dup NP_001341552.1:p.Asp290Ter nonsense NM_001354624.2:c.816dup NP_001341553.1:p.Asp273Ter nonsense NM_001354625.2:c.816dup NP_001341554.1:p.Asp273Ter nonsense NM_001354626.2:c.816dup NP_001341555.1:p.Asp273Ter nonsense NM_001354627.2:c.816dup NP_001341556.1:p.Asp273Ter nonsense NM_001354628.2:c.1890dup NP_001341557.1:p.Asp631Ter nonsense NM_001354629.2:c.1791dup NP_001341558.1:p.Asp598Ter nonsense NM_001354630.2:c.1732-840dup intron variant NC_000003.12:g.37047677dup NC_000003.11:g.37089168dup NG_007109.2:g.59328dup LRG_216:g.59328dup LRG_216t1:c.1890dup LRG_216p1:p.Asp631Ter - Protein change
- D390*, D631*, D598*, D273*, D290*, D533*
- Other names
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- Canonical SPDI
- NC_000003.12:37047675:TT:TTT
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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 |
5689 | 5749 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000164560.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2022 | RCV001213405.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV003454397.1 |
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
(Jun 04, 2014)
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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: SCV000215218.5
First in ClinVar: Mar 24, 2015 Last updated: Jun 22, 2020 |
Comment:
The c.1890dupT pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a duplication of T at nucleotide position 1890, causing a … (more)
The c.1890dupT pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a duplication of T at nucleotide position 1890, causing a translational frameshift with a predicted alternate stop codon. This mutation was identified in one individual of Argentinian descent suspected of Lynch syndrome (Valentin MD, Fam. Cancer 2011 Dec; 10(4):641-7.). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 11, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001385034.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 185190). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 185190). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 21681552, 25980754, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp631*) 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). (less)
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Pathogenic
(Jan 02, 2024)
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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: SCV000684778.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant inserts 1 nucleotide in exon 16 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant inserts 1 nucleotide in exon 16 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with Lynch syndrome (PMID: 21681552, 27606285) and in an individual with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). 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
(Jul 24, 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: SCV004189619.1
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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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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Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome. | Dominguez-Valentin M | Frontiers in oncology | 2016 | PMID: 27606285 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
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 |
Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals. | Valentin MD | Familial cancer | 2011 | PMID: 21681552 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
Text-mined citations for rs786201990 ...
HelpRecord last updated Sep 29, 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.