GeneBe

MEN1

protein-coding

menin 1

Gene summary

This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

MANE transcript

NM_001370259.2

Inheritance

AD

ClinVar variants

P:708U:1194B:812

Top phenotype

Multiple endocrine neoplasia type I; Hyperparathyroidism, familial primary

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr11:64,803,510-64,811,294

External References & Databases

Ensembl (ENSG00000133895)OMIM (613733)HGNC:7010GenCCUniProt (O00255)AlphaFoldClinVar (MEN1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pituitary gigantismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020479

Submitter: Orphanet

multiple endocrine neoplasia type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007540

Submitter: Orphanet

familial isolated hyperparathyroidismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015027

Submitter: Orphanet

multiple endocrine neoplasia type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007540

Submitter: G2P

multiple endocrine neoplasia type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007540

Submitter: Labcorp Genetics (formerly Invitae)

multiple endocrine neoplasia type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007540

Submitter: ClinGen

Multiple endocrine neoplasia type 1 (MEN1) is a complex syndrome defined by the neoplastic transformation of at least two endocrine organs, most frequently parathyroid glands, pancreatic islets, anterior pituitary and endocrine pancreas. There is abundant evidence published associating the MEN1 gene with multiple endocrine neoplasia type 1, since the gene-disease relationship was first proposed by Chandrasekharappa SC, et al., 1997 (PMID: 9103196). Multiple case level studies have been performed with MEN1 patients that have variants in the MEN1 gene. The variants include single amino acid changes or deletions that affect the stability of the protein and nonsense or frameshift LOF variants. A significant amount of case-level data is available; the maximum points for genetic evidence has been reached (12 points). Multiple mouse models of MEN1 have been established to show development of tumors consistent with MEN1 syndrome. In summary, MEN1 is definitively associated with the autosomal autosomal dominant Multiple Endocrine Neoplasia Type 1 syndrome. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

multiple endocrine neoplasia type 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007540

Submitter: Ambry Genetics

hereditary pheochromocytoma-paragangliomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Multiple endocrine neoplasia type I; Hyperparathyroidism, familial primaryAD

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: Surveillance and early detection of and treatment for neoplasms, as well as related sequelae may allow treatment (eg, with PPIs/somatostatin analogs, as well as appropriate and tailored surgical interventions and follow-up), and may decrease morbidity and mortality

Refs: 6108714; 2857681; 9215689; 9103196; 9236523; 9215690; 9463336; 9683585; 9554741; 9832038; 9506756; 9709923; 9792884; 10439966; 10193936; 11344233; 11739416; 11295574; 12417605; 12050235; 11836268; 12112656; 12791038; 15531478; 14871962; 15240620; 15292304; 14985373; 17879353; 20301710; 22522645; 22549346; 22581216; 22584706; 23052745; 23376981; 23443490; 23645327; 23652667; 23809488; 23919339; 23956349; 23961499; 24014011; 24037737; 24058102Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MEN1 variants in ClinVar

37 Conditions Cataloged
Multiple endocrine neoplasia, type 1Total: 2371
Hereditary cancer-predisposing syndromeTotal: 1752
not providedTotal: 422
not specifiedTotal: 131
MEN1-related disorderTotal: 122
HyperparathyroidismTotal: 26
Familial hyperparathyroidism or Hypocalciuric hypercalcaemiaTotal: 8
Pituitary adenoma 5, multiple typesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001370259.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
5
clinvar
9
clinvar
673
clinvar
32
clinvar
 719
missense
28
clinvar
163
clinvar
1167
clinvar
103
clinvar
3
clinvar
 1464
nonsense
104
clinvar
12
clinvar
2
clinvar
 118
start loss
4
clinvar
3
clinvar
 7
frameshift
269
clinvar
45
clinvar
11
clinvar
 325
splice donor/acceptor (+/-2bp)
42
clinvar
33
clinvar
5
clinvar
1
clinvar
 81
Total4472611194777352714

Highest pathogenic variant AF is 0.00024173524

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 105 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001370259.2RefSeqNP_001357188.29MANE Select
ENST00000450708.7EnsemblENSP00000394933.39MANE Select
NM_000244.4RefSeqNP_000235.39Standard
NM_001370251.2RefSeqNP_001357180.210Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cushing,s syndrome - Homo sapiens (human)
  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • Cell Cycle
  • Signaling by WNT
  • Signal Transduction

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • MAPK cascade
  • mitotic cell cycle
  • negative regulation of protein phosphorylation
  • osteoblast development

Molecular Function

  • four-way junction DNA binding
  • Y-form DNA binding
  • chromatin binding
  • double-stranded DNA binding
  • protein binding

Cellular Component

  • nuclear chromosome, telomeric region
  • chromatin
  • nuclear chromatin
  • nucleus
  • nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000337652
Coding exons
9
Length
7785
Individuals with no LoFs
125672
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125674
p
0.00000796
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.252003780.5300.00002413907
Missense (PolyPhen)50159.080.314311640
Synonymous0.7541531650.9250.00001061301
Loss of Function4.71127.80.03600.00000147290

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair. {ECO:0000250, ECO:0000269|PubMed:11274402, ECO:0000269|PubMed:11526476, ECO:0000269|PubMed:12837246, ECO:0000269|PubMed:12874027, ECO:0000269|PubMed:14992727}.;
Disease
DISEASE: Note=MEN1 inactivating mutations are responsible for hyperfunctioning of the parathyroid glands and subsequent primary hyperparathyroidism. Primary hyperparathyroidism can occur in isolation or in association with multiple endocrine neoplasia. {ECO:0000269|PubMed:10634381, ECO:0000269|PubMed:10664521, ECO:0000269|PubMed:12016470, ECO:0000269|PubMed:12699448, ECO:0000269|PubMed:9792884, ECO:0000269|PubMed:9843042, ECO:0000269|PubMed:9888389}.;

Intolerance Scores

RVIS EVS
-0.27
RVIS percentile EVS
34.6

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.991

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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