ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1546dup (p.Arg516fs)
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.1546dup (p.Arg516fs)
Variation ID: 279852 Accession: VCV000279852.44
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64804620-64804621 (GRCh38) [ NCBI UCSC ] 11: 64572092-64572093 (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 Apr 4, 2013 Mar 10, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370259.2:c.1546dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Arg516fs frameshift NM_000244.4:c.1561dup NP_000235.3:p.Arg521fs frameshift NM_001370251.2:c.1672dup NP_001357180.2:p.Arg558fs frameshift NM_001370260.2:c.1546dup NP_001357189.2:p.Arg516fs frameshift NM_001370261.2:c.1546dup NP_001357190.2:p.Arg516fs frameshift NM_001370262.2:c.1441dup NP_001357191.2:p.Arg481fs frameshift NM_001370263.2:c.1441dup NP_001357192.2:p.Arg481fs frameshift NM_130799.2:c.1546dupC frameshift NM_130799.3:c.1546dup NP_570711.2:p.Arg516fs frameshift NM_130800.3:c.1561dup NP_570712.2:p.Arg521fs frameshift NM_130801.3:c.1561dup NP_570713.2:p.Arg521fs frameshift NM_130802.3:c.1561dup NP_570714.2:p.Arg521fs frameshift NM_130803.3:c.1561dup NP_570715.2:p.Arg521fs frameshift NM_130804.3:c.1561dup NP_570716.2:p.Arg521fs frameshift NC_000011.10:g.64804627dup NC_000011.9:g.64572099dup NG_008929.1:g.11674dup NG_033040.1:g.3621dup LRG_509:g.11674dup LRG_509t2:c.1546dup LRG_509p2:p.Arg516fs - Protein change
- R481fs, R521fs, R558fs, R516fs
- Other names
- 1657insC
- Canonical SPDI
- NC_000011.10:64804620:GGGGGGG:GGGGGGGG
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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
Help
The frequency of the allele represented by this VCV record.
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- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
2415 | 2434 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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) |
no assertion criteria provided
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Dec 1, 1997 | RCV000018171.11 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 20, 2023 | RCV000269197.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV000491230.12 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV000548407.21 |
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
Help
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
Help
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
Help
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
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781725.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
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Pathogenic
(Jan 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001476547.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in … (more)
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. (less)
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Pathogenic
(Jul 28, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570981.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: MEN1 c.1546dupC (p.Arg516ProfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MEN1 c.1546dupC (p.Arg516ProfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.1e-05 in 237028 control chromosomes. c.1546dupC has been reported in the literature as a common pathogenic mutation in numerous individuals affected with Multiple Endocrine Neoplasia Type 1 and was shown to segregate with disease (examples: Kytola_2001, Bassett_1998, Romanet_2019, etc). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 03, 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: SCV000329424.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a … (more)
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: impaired nuclear localization of protein compared to wild-type (Ikeo 1999); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1561dup, c.1650insC, c.1657insC, and c.7773insC; This variant is associated with the following publications: (PMID: 9463336, 11836268, 20660572, 28701629, 9361035, 10993647, 17879353, 17065424, 15714081, 12652570, 10576763, 10812010, 10849016, 9709921, 12050235, 14985373, 11058905, 11524904, 15670192, 12112656, 9747036, 21340156, 27038812, 11034102, 15240620, 11303512, 19041010, 25291050, 9215689, 15635078, 9683585, 15730416, 22470073, 29036195, 30324798, 20367983, 12213668, 17853334, 23321498, 24915123, 10595737, 34160414) (less)
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Pathogenic
(Jan 24, 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: SCV000579621.6
First in ClinVar: Jun 25, 2017 Last updated: Apr 15, 2023 |
Comment:
The c.1546dupC pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of C at nucleotide position 1546, causing a … (more)
The c.1546dupC pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of C at nucleotide position 1546, causing a translational frameshift with a predicted alternate stop codon (p.R516Pfs*15). This mutation has been reported in several families affected with multiple endocrine neoplasia type 1 (MEN1) (Zha BB et al. Chinese Med J. 2010;123(5):569-573; Pieterman CR et al. Ann Surg. 2012 Jun;255(6):1171-8; Cardinal JW et al. J. Med. Genet., 2005 Jan;42:69-74; Pardi E et al. PLoS ONE. 2017 Oct;12(10):e0186485). This mutation was also reported in an early onset sporadic case of MEN1 (Boguszewski CL et al. Arq Bras Endocrinol Metabol. 2010 Nov;54(8):705-10) and in a patient with primary hyperparathyroidism (Lemos MC & Thakker RV Hum. Mutat. 2008 Jan; 29(1):22-32). Of note, this mutation is also designated as c.1546_1547insC, p.Arg521fsX15, and c.1561dup (p.Arg521fs) in the published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 20, 2023)
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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: SCV002047850.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
Comment:
The MEN1 c.1546dup; p.Arg516ProfsTer15 variant (rs767319284), also known as 1561dupC, 1650insC, 1656dupC, or 1657insC, is reported in the literature in multiple individuals and families affected … (more)
The MEN1 c.1546dup; p.Arg516ProfsTer15 variant (rs767319284), also known as 1561dupC, 1650insC, 1656dupC, or 1657insC, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Cardinal 2005, de Laat 2014, Ebeling 2004, Karageorgiadis 2015, Kytola 2001, Pieterman 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 279852). 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 protein, and other downstream pathogenic truncating variants have been reported in families with multiple endocrine neoplasia type 1 (Cardinal 2005, Pieterman 2012). Based on available information, this variant is considered to be pathogenic. References: Cardinal JW et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet. 2005 Jan;42(1):69-74. PMID: 15635078. de Laat JM et al. Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients. J Clin Endocrinol Metab. 2014 Sep;99(9):3325-33. PMID: 24915123. Ebeling T et al. Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations. J Clin Endocrinol Metab. 2004 Jul;89(7):3392-6. Karageorgiadis AS et al. Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. J Clin Endocrinol Metab. 2015 Jan;100(1):141-8. PMID: 15240620. Kytola S et al. Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. J Med Genet. 2001 Mar;38(3):185-9. PMID: 11303512. Pieterman CR et al. Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg. 2012 Jun;255(6):1171-8. PMID: 22470073. (less)
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Pathogenic
(Jan 16, 2024)
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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: SCV000628059.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg516Profs*15) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg516Profs*15) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the MEN1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689, 15635078, 21340156, 22470073, 24915123, 25291050). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1650insC, c.1561dup (p.Arg521fs), c.1561dupC, and c.1546dupC.. ClinVar contains an entry for this variant (Variation ID: 279852). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Arg516Glyfs*43) have been determined to be pathogenic (PMID: 9215689, 12112656, 12213668, 15670192, 17065424, 17853334, 23321498). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248412.19
First in ClinVar: May 12, 2020 Last updated: Mar 10, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 1997)
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no assertion criteria provided
Method: literature only
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CARCINOID TUMOR OF LUNG
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038450.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Lung carcinoids occur sporadically and rarely in association with MEN1 (see 131100). Debelenko et al. (1997) studied 11 sporadic lung carcinoids for LOH in 1 … (more)
Lung carcinoids occur sporadically and rarely in association with MEN1 (see 131100). Debelenko et al. (1997) studied 11 sporadic lung carcinoids for LOH in 1 locus and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from an MEN1 patient was studied. In 4 of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All 4 tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1-bp insertion (1650insC) , a 1-bp deletion, a 13-bp deletion, and a single nucleotide substitution affecting a donor splice site. Each mutation predicted truncation or potentially complete loss of MEN1. The remaining 7 tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at 11q13 and a complex germline MEN1 gene mutation. The findings of this study represented the first defined genetic alteration in carcinoids. (less)
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Pathogenic
(Jul 01, 2004)
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no assertion criteria provided
Method: literature only
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038468.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2017 |
Comment on evidence:
Ebeling et al. (2004) used church records and MEN1 (131100) family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 … (more)
Ebeling et al. (2004) used church records and MEN1 (131100) family information to detect founder couples for the 2 prevailing mutations in Northern Finland, 1466del12 (613733.0032) and 1657insC. Four families with the 1657incC mutation could be traced back to a couple living 200 kilometers northeast of Oulu born in 1844 and 1846, and not farther than only 4 generations from the youngest. The authors noted that while the most prevalent mutation (1466del12; 613733.0032) is a unique Finnish mutation, the 1657delC mutation seems to be a hotspot, as it has been found in 5 different MEN1 populations (Guo and Sawicki, 2001). (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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UMD-MEN1 Database: An Overview of the 370 MEN1 Variants Present in 1676 Patients From the French Population. | Romanet P | The Journal of clinical endocrinology and metabolism | 2019 | PMID: 30339208 |
Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. | Carvalho RA | European journal of endocrinology | 2018 | PMID: 30324798 |
Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. | Pardi E | PloS one | 2017 | PMID: 29036195 |
Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. | Karageorgiadis AS | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 25291050 |
Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients. | de Laat JM | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24915123 |
Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. | Cuny T | European journal of endocrinology | 2013 | PMID: 23321498 |
Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. | Pieterman CR | Annals of surgery | 2012 | PMID: 22470073 |
Application of genetic testing to define the surgical approach in a sporadic case of multiple endocrine neoplasia type 1. | Boguszewski CL | Arquivos brasileiros de endocrinologia e metabologia | 2010 | PMID: 21340156 |
Identification of multiple endocrine neoplasia type 1 in patients with apparent sporadic primary hyperparathyroidism. | Yip L | Surgery | 2008 | PMID: 19041010 |
Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. | Lemos MC | Human mutation | 2008 | PMID: 17879353 |
Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. | Schaaf L | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2007 | PMID: 17853334 |
Rapid mutation screening for HRPT2 and MEN1 mutations associated with familial and sporadic primary hyperparathyroidism. | Howell VM | The Journal of molecular diagnostics : JMD | 2006 | PMID: 17065424 |
Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. | Ellard S | Clinical endocrinology | 2005 | PMID: 15670192 |
A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. | Cardinal JW | Journal of medical genetics | 2005 | PMID: 15635078 |
Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations. | Ebeling T | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15240620 |
Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. | Villablanca A | European journal of endocrinology | 2002 | PMID: 12213668 |
Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. | Wautot V | Human mutation | 2002 | PMID: 12112656 |
Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1. | Guo SS | Molecular endocrinology (Baltimore, Md.) | 2001 | PMID: 11579199 |
Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. | Kytölä S | Journal of medical genetics | 2001 | PMID: 11303512 |
Characterization of mutations in patients with multiple endocrine neoplasia type 1. | Bassett JH | American journal of human genetics | 1998 | PMID: 9463336 |
Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. | Debelenko LV | Human molecular genetics | 1997 | PMID: 9361035 |
Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. | Agarwal SK | Human molecular genetics | 1997 | PMID: 9215689 |
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Text-mined citations for rs767319284 ...
HelpRecord last updated Mar 23, 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.
NCBI staff determined the location of this allele from the gel in Figure 2 of the paper by Debelenko et al., 1997 (PubMed 9361035).