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TMEM127 gene - Cancer risk, management, and testing for genetic mutations

Associated Syndrome Name: Hereditary pheochromocytoma-paraganglioma syndrome (hereditary PPGL syndrome)

TMEM127 Summary Cancer Risk Table

Cancer	Genetic Cancer Risk
Endocrine	High Risk

TMEM127 gene Overview

Hereditary pheochromocytoma-paraganglioma syndrome (hereditary PPGL syndrome) 1, 2, 3, 4, 5, 6, 7

Individuals with mutations in TMEM127 have hereditary pheochromocytoma-paraganglioma syndrome (hereditary PPGL syndrome).
Individuals with hereditary PPGL syndrome due to mutations in TMEM127 have a high risk for cancers of the nervous system (paragangliomas), which are most often in the abdomen, but can also be in the head, neck, or upper body. There is also a high risk for paragangliomas of the adrenal gland (pheochromocytomas). Paragangliomas and pheochromocytomas can develop at young ages.
Paragangliomas and pheochromocytomas in individuals with hereditary PPGL syndrome often secrete hormones that can cause symptoms such as high blood pressure, rapid and/or abnormal heartbeat, headaches, sweating, nausea, fatigue and anxiety.
Individuals with hereditary PPGL syndrome due to TMEM127 mutations have an elevated risk for renal cancer. The exact level of these risks is not known.
Other genes associated with hereditary PPGL syndrome have an elevated risk for gastrointestinal stromal tumors (GIST). However, the data are not conclusive as to whether TMEM127 mutations also cause an increased risk for these or other cancers at this time.
Although there are high risks for cancers and other medical conditions in individuals with hereditary PPGL syndrome, it may be possible to reduce these risks with appropriate medical management. Guidelines for the medical management of patients with hereditary PPGL syndrome have been developed by the National Comprehensive Cancer Network (NCCN), American Association for Cancer Research (AACR), and international consensus. These are summarized below. Since hereditary PPGL syndrome is a complex condition, and management recommendations are likely to change over time, patients with TMEM127 mutations and a diagnosis of hereditary PPGL syndrome should be managed by a multidisciplinary team with expertise in medical genetics and the prevention and treatment of the complications associated with this condition.

TMEM127 gene Cancer Risk Table

Cancer Type	Age Range	Cancer Risk	Risk for General Population
Paraganglioma/Pheochromocytoma	To age 201, 2	Up to 4%	<0.1%
	To age 651, 2	32%-83%	<0.1%

TMEM127 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type	Procedure	Age to Begin	Frequency (Unless otherwise indicated by findings)
Paraganglioma/Pheochromocytoma	Clinical monitoring, including blood pressure measurement4, 6	10 to 15 years	Annually
	Biochemical screening of blood and urine4, 6	10 to 15 years	Every 1 to 3 years, depending on symptoms and findings, or prior to any surgical procedure
	Whole-body MRI. If not available, consider chest CT and MRI of abdomen, pelvis, skull base, and neck.4, 6, 7	10 to 21 years	Every 2 to 5 years

Benefits of Testing for TMEM127 Gene Mutations:

Testing for TMEM127 gene mutations with the MyRisk^® Hereditary Cancer Test with RiskScore^® provides critical insights to patients and providers about potential hereditary cancer risk. Identifying a TMEM127 gene mutation can help clarify whether a patient is at increased risk for certain cancers and guide proactive, personalized care planning. With definitive answers from the MyRisk Test, healthcare providers can better tailor screening, prevention, and management strategies, while patients gain clarity and confidence about their hereditary cancer risk. In addition, understanding a TMEM127 gene mutation allows family members to consider their own hereditary cancer risk, supporting informed decision-making and potentially life-saving early interventions. Learn more about the MyRisk^® with RiskScore^® Hereditary Cancer Test.

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the TMEM127 gene.

This patient's relatives are at risk for carrying the same mutation(s) and associated cancer risks as this patient. Cancer risks for females and males who have this/these mutation(s) are provided below.

Family members should talk to a healthcare provider about genetic testing. Close relatives such as parents, children, brothers and sisters have the highest chance of having the same mutation(s) as this patient. Other more distant relatives such as cousins, aunts, uncles, and grandparents also have a chance of carrying the same mutation(s). Testing of at-risk relatives can identify those family members with the same mutation(s) who may benefit from surveillance and early intervention.

It is appropriate to offer genetic counseling to individuals with hereditary PPGL syndrome who are of reproductive age to discuss reproductive risks and options. There are additional considerations before and during pregnancy for individuals with hereditary PPGL syndrome.5

Since TMEM127 mutations carry a risk for complications in children and some screenings are recommended to begin as early as age 10 years, consideration should be given to mutation testing in childhood.2, 5

References

Bausch B, et al. Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention. JAMA Oncol. 2017 Sep 1;3(9):1204-1212. PMID: 28384794.

Toledo SP, et al. Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation. J Clin Endocrinol Metab. 2015 Feb;100(2):E308-18. PMID: 25389632.

Qin Y, et al. The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function. Hum Mol Genet. 2014 May 1;23(9):2428-39. PMID: 24334765.

Casey RT, et al. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. Nat Rev Endocrinol. 2024 Aug 15. PMID: 39147856.

Else T, et al. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2023 Sep 21. In: Adam MP, et al., editors. GeneReviews^® [Internet]. PMID: 20301715.

Bergsland E, et al. NCCN Clinical Practice Guidelines in Oncology^®: Neuroendocrine and Adrenal Tumors. V 2.2025. May 28. Available at https://www.nccn.org.

Greer MC, et al. Update on Whole-Body MRI Surveillance for Pediatric Cancer Predisposition Syndromes. Clin Cancer Res. 2024 Nov 15;30(22):5021-5033. PMID: 39287924.

Last Updated on 15-Sep-2025