ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2196dup (p.His733fs)
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.2196dup (p.His733fs)
Variation ID: 2674523 Accession: VCV002674523.2
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37050575-37050576 (GRCh38) [ NCBI UCSC ] 3: 37092066-37092067 (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 Dec 25, 2023 Feb 20, 2024 Jul 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.2196dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.His733fs frameshift NM_001167617.3:c.1902dup NP_001161089.1:p.His635fs frameshift NM_001167618.3:c.1473dup NP_001161090.1:p.His492fs frameshift NM_001167619.3:c.1473dup NP_001161091.1:p.His492fs frameshift NM_001258271.2:c.1989dup NP_001245200.1:p.His664fs frameshift NM_001258273.2:c.1473dup NP_001245202.1:p.His492fs frameshift NM_001258274.3:c.1473dup NP_001245203.1:p.His492fs frameshift NM_001354615.2:c.1473dup NP_001341544.1:p.His492fs frameshift NM_001354616.2:c.1473dup NP_001341545.1:p.His492fs frameshift NM_001354617.2:c.1473dup NP_001341546.1:p.His492fs frameshift NM_001354618.2:c.1473dup NP_001341547.1:p.His492fs frameshift NM_001354619.2:c.1473dup NP_001341548.1:p.His492fs frameshift NM_001354620.2:c.1902dup NP_001341549.1:p.His635fs frameshift NM_001354621.2:c.1173dup NP_001341550.1:p.His392fs frameshift NM_001354622.2:c.1173dup NP_001341551.1:p.His392fs frameshift NM_001354623.2:c.1173dup NP_001341552.1:p.His392fs frameshift NM_001354624.2:c.1122dup NP_001341553.1:p.His375fs frameshift NM_001354625.2:c.1122dup NP_001341554.1:p.His375fs frameshift NM_001354626.2:c.1122dup NP_001341555.1:p.His375fs frameshift NM_001354627.2:c.1122dup NP_001341556.1:p.His375fs frameshift NM_001354628.2:c.2103dup NP_001341557.1:p.His702fs frameshift NM_001354629.2:c.2097dup NP_001341558.1:p.His700fs frameshift NM_001354630.2:c.2031dup NP_001341559.1:p.His678fs frameshift NC_000003.12:g.37050578dup NC_000003.11:g.37092069dup NG_007109.2:g.62229dup LRG_216:g.62229dup LRG_216t1:c.2196dup LRG_216p1:p.His733Thrfs - Protein change
- H375fs, H392fs, H492fs, H635fs, H664fs, H678fs, H700fs, H702fs, H733fs
- Other names
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- Canonical SPDI
- NC_000003.12:37050575:AAA:AAAA
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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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- Links
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 |
5622 | 5677 |
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) |
criteria provided, single submitter
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Jul 25, 2023 | RCV003452718.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2023 | RCV003759866.1 |
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
(Jul 25, 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: SCV004186396.1
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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Pathogenic
(Jan 26, 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: SCV004437710.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His733Thrfs*13) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the MLH1 protein. (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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[Founder mutation in Lynch syndrome]. | Cajal AR | Medicina | 2016 | PMID: 27295708 |
A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns. | Borelli I | Familial cancer | 2014 | PMID: 24802709 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Mismatch repair gene mutations in Chinese HNPCC patients. | Sheng JQ | Cytogenetic and genome research | 2008 | PMID: 18931482 |
Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer. | Han HJ | Journal of the National Cancer Institute | 1996 | PMID: 8797773 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 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.