• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit


Associated disorders

The TMEM127 gene is associated with autosomal dominant hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (MedGen UID: 18419).

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The TMEM127 gene is a tumor suppressor that encodes a transmembrane protein associated with several cellular organelles and regulates protein synthesis and cell survival.

TMEM127: Hereditary Paraganglioma Pheochromocytoma
MedGen UID: 18419

Clinical condition
The TMEM127 gene is associated with the development of pheochromocytomas (PCCs) and/or paragangliomas (PGLs) as seen in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 20301715, 22419703, 21156949, 20154675). It has also been suggested that TMEM127 variants are associated with other cancers; however, the data is currently limited and emerging (PMID: 25770152, 25800244). The clinical presentation is highly variable and may be difficult to predict. While an individual with a TMEM127 pathogenic variant will not necessarily develop cancer in their lifetime, the risk for cancer is increased over the general population risk.

Paragangliomas (PGL) 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 that develop in the head and neck are called head-and-neck paragangliomas (HNP). PGLs located outside the head and neck most commonly occur in the adrenal glands and are called pheochromocytomas (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 TMEM127, that can result in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 24903423, 24893135, 20301715, 23512077, 22419703, 21156949, 20154675).

Current literature suggests that individuals with a pathogenic TMEM127 variant most often present with benign, unilateral PCCs mimicking sporadic PCC, but less commonly can also develop either bilateral PCCs, HNPs or abdominal extra-adrenal PGLs (PMID: 24899893, 26347711). The risk of malignancy appears to be low (possibly as low as ~1%) (PMID: 24899893, 26347711, 20301715). Affected individuals are typically diagnosed later in life (the mean age at diagnosis is 42 years), and there may be no other significant family history (PMID: 24899893, 26347711, 24523625).

Gene information
TMEM127 is a tumor suppressor gene playing a role in cell signaling associated with kinase receptor signals. In addition, TMEM127 is a negative regulator of mTOR, which is a member of the phosphatidylinositol-3-kinase (PI3K)-related kinase family that promotes cell growth, angiogenesis, cell survival, and protein translation (PMID: 26347711, 25770152, 26839173). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain types of cancers.

Pathogenic variants in TMEM127 have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. While many cases are inherited from a parent, some cases can occur spontaneously. This means that an individual with a pathogenic variant has parents who do not have it. However, that individual now has a 50% risk of passing it on to their offspring.

It is suggested that individuals with hereditary paraganglioma-pheochromocytoma syndrome, 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). Although there is currently no clear consensus regarding a screening and surveillance protocol for individuals with pathogenic TMEM127 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):

RecommendationTMEM127 Screening
Age to begin screening 5–10 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 is important to note that individuals with hereditary PGL/PCC syndromes may be at a greater risk of developing PGL and/or PCC when living in higher altitudes or chronically exposed to hypoxic conditions (PMID: 20301715). There is 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 TMEM127 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, making 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 as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant in TMEM127 is present is advantageous. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant TMEM127 data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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
TMEM127 NM_017849.3