• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The MAX gene is associated with autosomal dominant hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (MedGen UID: 313270).

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The MAX gene encodes a transcription factor that forms homodimers or heterodimers with Mad, Mxi1 and Myc, which are involved in regulating cell proliferation, differentiation, and apoptosis.

MAX: hereditary paraganglioma pheochromocytoma
MedGen UID: 313270

Clinical condition
The MAX gene is associated with the development of pheochromocytomas (PCCs) and/or paragangliomas (PGLs), as seen in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 20301715, 23666964, 21685915). It is unclear if pathogenic MAX variants are associated with other cancers, as the data are currently limited and emerging. The clinical presentation is highly variable and may be difficult to predict. While an individual with a MAX pathogenic variant will not necessarily develop cancer in their lifetime, the risk for cancer is increased over the general population risk.

PGLs are rare, adult-onset, typically benign neuroendocrine tumors that arise from paraganglia. Paraganglia are a collection of neuroendocrine tissues that are distributed throughout the body, from the middle ear and skull base to the pelvis. PGLs located in the head and neck are called head-and-neck paragangliomas (HNP). PGLs outside of the head and neck most commonly occur in the adrenal glands and are called PCC (also known as chromaffin tumors). PCCs are catecholamine-secreting PGLs that are confined to the adrenal medulla, as defined by the The World Health Organization Tumor Classification; however, this term may also be used to refer to catecholamine-producing PGLs regardless of whether they are adrenal or extra-adrenal (PMID: 24899893). These lesions can cause excessive production of adrenal hormones, resulting in hypertension, headaches, tachycardia, anxiety, and sweaty or clammy skin in some individuals (PMID: 21771581, 24893135, 20301715). Most cases of PGL and PCC are sporadic, but approximately one-third are familial and due to an identifiable pathogenic variant in a susceptibility gene, such as MAX, that can result in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 24903423, 24893135, 20301715, 23512077).

Pathogenic variants in MAX predispose primarily to PCCs, although a subset of cases will also develop PGLs (PMID: 20301715). Incidents of PGLs have occurred in individuals initially diagnosed with PCC (PMID: 22452945). Hereditary PCCs and/or PGLs due to pathogenic variants in MAX are infrequent, have a median age at diagnosis of 34 years (13-58), and are often observed in individuals with a positive family history (PMID: 24893135). Even though the number of affected individuals is limited, there appears to be a tendency toward bilateral or multiple tumors within the same gland (PMID: 24523625, 22452945). It is unclear if there is a risk of malignancy because the evidence in the literature is conflicting, but it has been suggested that the risk may be up to 10% (PMID: 24523625, 26347711, 22452945, 26839173).

Gene information
MAX (myc-associated factor X) is a tumor-suppressor gene that is part of the MYC-MAX-MXD1 complex, which regulates cell proliferation, differentiation, and apoptosis (PMID: 24899893, 24523625, 26839173, UniProtKB – P61244 (MAX_HUMAN). Accessed September 2015). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers may be increased.

The MAX gene follows traditional Mendelian autosomal dominant inheritance, although there appears to be demonstration of parent-of-origin effects: MAX generally causes disease when the pathogenic variant is inherited from the father. The risk of clinical disease after maternal transmission appears to be very low (PMID: 24899893, 24903423, 20301715). The offspring of an individual with a pathogenic MAX variant, regardless of parental origin, has a 50% risk of passing the variant on to their offspring. The underlying cause of this parent-of-origin effect has yet to be elucidated (PMID: 26113606, 26067997). With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant.

It is suggested that individuals with a pathogenic MAX variant, along with their at-risk relatives, have regular clinical monitoring by a physician or medical team with expertise in the treatment of hereditary PGL/PCC syndromes. A consultation with an endocrine surgeon, endocrinologist, and otolaryngologist is also recommended to establish an individualized care plan (PMID: 20301715).

Screening should begin between five and ten years of age, or at least ten years before the earliest age at diagnosis in the family (PMID: 24903423, 20301715, 24523625, 21771581). Although there is currently no clear consensus regarding a screening and surveillance protocol for individuals with pathogenic MAX variants, lifelong annual biochemical and clinical surveillance has been suggested (PMID: 20301715, 24893135, 24523625, 25385035):

  • Physical exam and blood pressure at the time of diagnosis and then every 6-12 months
  • 24-hour urinary excretion of fractionated metanephrines and catecholamines and/or plasma fractionated metanephrines at least annually to detect metastatic disease, tumor recurrence, or development of additional tumors
    • Follow up with imaging by CT, MRI, 123I-MIBG (metaiodobenzylguanidine) scintigraphy, or FDG-PET if the fractionated metanephrine and/or catecholamine levels become elevated, or if the original tumor had minimal or no catecholamine/fractionated metanephrine excess.
  • Periodic MRI or CT inclusive of head, neck, thorax, abdomen, and pelvic areas
    • In order to minimize radiation exposure, MRI may be the preferable imaging modality with CT and nuclear imaging reserved to further characterize detected tumors
    • Imaging modalities should be at the discretion of the managing provider due to conflicting data regarding the utility and efficacy of the various options (PMID: 25385035)
  • Evaluation of cases with extra-adrenal sympathetic PGL and PCC for blood pressure elevations, tachycardia, and other signs and symptoms of catecholamine hypersecretion
  • Medical genetics consultation

Summary of Medical Management and Surveillance Recommendations (PMID: 24893135, 20301715, 25385035)

Recommendation MAX Screening
Age to begin screening 5 years–10 years
Physical exam and blood pressure Every 6–12 months
Urinary excretion of fractionated metanephrines and catecholamines in 24 hours Annually
Whole body MRI Every 2-3 years (PMID: 25385035

It remains unclear whether imaging studies should be conducted as frequently in childhood as in adulthood (PMID: 24523625).

It is important to note that individuals with hereditary PGL/PCC syndromes may be at a greater risk of developing PGL or PCC when living in higher altitudes or when chronically exposed to hypoxic conditions (PMID: 20301715). There are data suggesting such risks in individuals with pathogenic variants in SDHA, SDHB, SDHC, SDHD, and SDHAF2; however, it is unclear if this applies specifically to individuals with pathogenic MAX variants (PMID: 20301715).

Syndromes associated with a predisposition to PGLs and PCCs may be associated with high morbidity and significant complications, which can lead to decreased lifespan and quality of life, therefore early screening and therapeutic interventions are imperative. However, the natural history of hereditary paraganglioma-pheochromocytoma syndrome is variable and continues to evolve. This can often result in significant uncertainty regarding long-term prognosis. Targeted genetic counseling may help patients cope with this diagnosis while keeping them an active participant in the management of their condition (PMID: 24854530). In addition, the clinical manifestations of PGLs and PCCs are broad; many symptoms can mimic minor ailments such as headaches and palpitations. Once a pathogenic variant has been identified, patients should be encouraged to have a low threshold for contacting their healthcare provider for further evaluation of unusual symptoms (PMID: 24854530).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding MAX are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: March 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
MAX NM_002382.4