ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1609del (p.Val537fs)
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_001370259.2(MEN1):c.1609del (p.Val537fs)
Variation ID: 1459608 Accession: VCV001459608.11
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64804558 (GRCh38) [ NCBI UCSC ] 11: 64572030 (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 28, 2022 Feb 14, 2024 Feb 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370259.2:c.1609del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Val537fs frameshift NM_000244.4:c.1624del NP_000235.3:p.Val542fs frameshift NM_001370251.2:c.1735del NP_001357180.2:p.Val579fs frameshift NM_001370260.2:c.1609del NP_001357189.2:p.Val537fs frameshift NM_001370261.2:c.1609del NP_001357190.2:p.Val537fs frameshift NM_001370262.2:c.1504del NP_001357191.2:p.Val502fs frameshift NM_001370263.2:c.1504del NP_001357192.2:p.Val502fs frameshift NM_130799.3:c.1609del NP_570711.2:p.Val537fs frameshift NM_130800.3:c.1624del NP_570712.2:p.Val542fs frameshift NM_130801.3:c.1624del NP_570713.2:p.Val542fs frameshift NM_130802.3:c.1624del NP_570714.2:p.Val542fs frameshift NM_130803.3:c.1624del NP_570715.2:p.Val542fs frameshift NM_130804.3:c.1624del NP_570716.2:p.Val542fs frameshift NC_000011.10:g.64804559del NC_000011.9:g.64572031del NG_008929.1:g.11737del NG_033040.1:g.3684del LRG_509:g.11737del LRG_509t2:c.1609del - Protein change
- V542fs, V537fs, V502fs, V579fs
- Other names
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- Canonical SPDI
- NC_000011.10:64804557:CC: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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- 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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MEN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2417 | 2434 |
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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Jun 9, 2021 | RCV001963123.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 21, 2023 | RCV002388935.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 19, 2022 | RCV003120788.3 |
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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Likely pathogenic
(May 19, 2022)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800002.1
First in ClinVar: Feb 13, 2023 Last updated: Feb 13, 2023 |
Comment:
The MEN1 c.1609delG; p.Val537CysfsTer22 variant is reported in the literature in an individual undergoing genetic testing for multiple endocrine neoplasia type 1 (Klein 2005) and … (more)
The MEN1 c.1609delG; p.Val537CysfsTer22 variant is reported in the literature in an individual undergoing genetic testing for multiple endocrine neoplasia type 1 (Klein 2005) and is reported as pathogenic in the ClinVar database (Variation ID: 1459608). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated MEN1 protein. Additionally, several downstream truncating variants have been described in individuals with multiple endocrine neoplasia type 1 (Giraud 1998, Klein 2005, Romanet 2019) and this region is critical for protein function (Nelakurti 2020). Based on available information, this variant is classified as likely pathogenic. References: Giraud S et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998 Aug;63(2):455-67. PMID: 9683585. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. PMID: 15714081. Nelakurti DD et al. Comprehensive Analysis of MEN1 Mutations and Their Role in Cancer. Cancers (Basel). 2020 Sep 14;12(9):2616. PMID: 32937789. Romanet P et al. UMD-MEN1 Database: An Overview of the 370 MEN1 Variants Present in 1676 Patients From the French Population. J Clin Endocrinol Metab. 2019 Mar 1;104(3):753-764. PMID: 30339208. (less)
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Pathogenic
(Feb 21, 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: SCV002703921.2
First in ClinVar: Nov 29, 2022 Last updated: Apr 15, 2023 |
Comment:
The c.1609delG pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 1609, causing … (more)
The c.1609delG pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 1609, causing a translational frameshift with a predicted alternate stop codon (p.V537Cfs*22). This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 74 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, designated as a deletion creating a frameshift at codon 536, was reported in an individual who underwent MEN1 testing due to clinical suspicion of multiple endocrine neoplasia type 1 (Klein RD et al. Genet Med, 2005 Feb;7:131-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002242042.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MEN1 protein. Other variant(s) that disrupt this region … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MEN1 protein. Other variant(s) that disrupt this region (p.Thr580Argfs*8) have been determined to be pathogenic (PMID: 15331604, 16449969). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with clinical features of MEN1-related conditions (PMID: 15714081). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val537Cysfs*22) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 74 amino acid(s) of the MEN1 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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Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. | La P | Oncogene | 2006 | PMID: 16449969 |
Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. | Klein RD | Genetics in medicine : official journal of the American College of Medical Genetics | 2005 | PMID: 15714081 |
Direct binding of DNA by tumor suppressor menin. | La P | The Journal of biological chemistry | 2004 | PMID: 15331604 |
Text-mined citations for rs2136083128 ...
HelpRecord last updated Feb 20, 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.