GeneBe

MAX

protein-coding

MYC associated factor X, the group of Basic helix-loop-helix proteins

Gene summary

The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. Myc is an oncoprotein implicated in cell proliferation, differentiation and apoptosis. The homodimers and heterodimers compete for a common DNA target site (the E box) and rearrangement among these dimer forms provides a complex system of transcriptional regulation. Mutations of this gene have been reported to be associated with hereditary pheochromocytoma. A pseudogene of this gene is located on the long arm of chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

MANE transcript

NM_002382.5

Inheritance

AD

ClinVar variants

P:58U:289B:136

Top phenotype

Pheochromocytoma

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr14:65,006,174-65,102,695

External References & Databases

Ensembl (ENSG00000125952)NCBI Gene (4149)OMIM (154950)HGNC:6913GenCCUniProt (P61244)AlphaFoldClinVar (MAX)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~96.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polydactyly-macrocephaly syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0958227

Submitter: Ambry Genetics

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

pheochromocytomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: G2P

hereditary pheochromocytoma-paragangliomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: ClinGen

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] describes susceptibility to pheochromocytoma and paraganglioma with autosomal dominant inheritance. The MAX gene [MIM# 154950] -MYC associated factor X- is one of the susceptibility genes resulting in genetic predisposition to PCC, mostly in patients without familial antecedents, probably due to a paternal transmission effect [PMID 21685915 and 22452945]. MAX was first reported in relation to PGL/PCC in 2011 [Comino-Méndez I et al., PMID: 21685915]. Genetic evidence includes loss of function and missense variants in MAX found in Hereditary PCC with missense variants likely being the dominant negative effect [PMID: 26070438]. Genetic evidence was scored for loss of function variants [PMID 21685915, 22452945 and 28384794]. Missense variants and deletions are also reported but not used for this curation [PMID: 26670126 and 23666964]. Experimental evidence demonstrated loss MAX gene expression and loss of heterozygosity (LOH) in patient tumors carrying LoF variants [PMID: 21685915]. Loss of functional MAX expression in a Rat Pheochromocytoma (PCC) cell line (PC12) and reduction of cell proliferation by reintroducing MAX expression [PMID: 7791753], which showed MAX is a tumor suppressor gene. Luciferase reporter activity assays with 9 missense variants confirmed the dominant negative mechanism in pathogenesis of hereditary PCC [PMID: 26070438]. The encoded MAX protein is the most conserved dimerization component of the MYC-MAX-MXD1 network of basic helix-loop-helix leucine zipper (bHLHZ) transcription factors that regulate cell proliferation, differentiation, and apoptosis. MAX is definitely associated with autosomal dominant HPGL/PCC syndrome, most commonly pheochromocytoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

pheochromocytomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: Labcorp Genetics (formerly Invitae)

pheochromocytomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: Ambry Genetics

syndromic diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

PheochromocytomaAD

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal

Intervention: Oncologic

Rationale: Surveillance and/or awareness of cancer risk may allow early diagnosis and treatment of neoplasms, which may may reduce morbidity and mortality

Refs: 21685915; 38141607Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAX variants in ClinVar

10 Conditions Cataloged
Hereditary cancer-predisposing syndromeTotal: 405
Hereditary pheochromocytoma and paragangliomaTotal: 404
PheochromocytomaTotal: 89
not providedTotal: 75
MAX-related disorderTotal: 25
not specifiedTotal: 21
MULTIPLE ENDOCRINE NEOPLASIA, TYPE VTotal: 7
Polydactyly-macrocephaly syndromeTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002382.5. 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
4
clinvar
125
clinvar
3
clinvar
 132
missense
7
clinvar
271
clinvar
8
clinvar
 286
nonsense
11
clinvar
2
clinvar
3
clinvar
 16
start loss
3
clinvar
1
clinvar
1
clinvar
 5
frameshift
17
clinvar
4
clinvar
6
clinvar
 27
splice donor/acceptor (+/-2bp)
6
clinvar
7
clinvar
4
clinvar
 17
Total37212891333483

Highest pathogenic variant AF is 7.2611624e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002382.5RefSeqNP_002373.35MANE Select
ENST00000358664.9EnsemblENSP00000351490.45MANE Select
NM_001271068.2RefSeqNP_001257997.13Standard
NM_001271069.2RefSeqNP_001257998.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
maxDanio rerio

Structure: thrombocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Small cell lung cancer - Homo sapiens (human)
  • MAPK signaling pathway - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)
  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • EGF-Core

Biological Process

  • G1/S transition of mitotic cell cycle
  • negative regulation of transcription by RNA polymerase II
  • transcription by RNA polymerase II
  • cellular response to starvation
  • response to insulin

Molecular Function

  • RNA polymerase II regulatory region sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription repressor activity, RNA polymerase II-specific
  • DNA binding
  • DNA-binding transcription factor activity

Cellular Component

  • nuclear chromatin
  • nucleus
  • nucleoplasm
  • cytoplasm
  • PML body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000358664
Coding exons
5
Length
96522
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
3
Defined
125742
p
0.0000119
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.814594.60.4760.000006161064
Missense (PolyPhen)1033.5490.29807356
Synonymous0.5603236.30.8820.00000218288
Loss of Function2.68110.30.09736.40e-7103

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcription regulator. Forms a sequence-specific DNA- binding protein complex with MYC or MAD which recognizes the core sequence 5'-CAC[GA]TG-3'. The MYC:MAX complex is a transcriptional activator, whereas the MAD:MAX complex is a repressor. May repress transcription via the recruitment of a chromatin remodeling complex containing H3 'Lys-9' histone methyltransferase activity. Represses MYC transcriptional activity from E-box elements. {ECO:0000269|PubMed:26070438}.;
Disease
DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:21685915, ECO:0000269|PubMed:22452945, ECO:0000269|PubMed:26070438}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.573

Intolerance Scores

LoFtool
0.156
RVIS EVS
-0.23
RVIS percentile EVS
36.86

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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