Invitae Hereditary Paraganglioma-Pheochromocytoma Panel


Test description

The Invitae Hereditary Paraganglioma-Pheochromocytoma Panel analyzes up to 14 genes that are associated with an increased risk for hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC). Individuals with pathogenic variants in these genes have an increased risk for paragangliomas and/or pheochromocytomas, which may or may not be malignant. Some of the genes on this panel are also associated with gastrointestinal stromal tumors (GIST); they may be related to other cancers as well.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (10 genes)


SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.

Add-on preliminary-evidence genes (4 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.


  • Carney-Stratakis syndrome (CSS)
  • Hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC)
  • Multiple endocrine neoplasia type 2 (MEN2)
  • Neurofibromatosis type 1 (NF1)
  • von Hippel-Lindau syndrome (VHL)

Paragangliomas are rare, adult-onset neuroendocrine tumors that arise from paraganglia and may or may not be malignant. Paraganglia are a collection of neuroendocrine tissues that are distributed throughout the body, from the middle ear and the skull base (called head and neck paragangliomas or HNP) to the pelvis. Paragangliomas located outside the head and neck most commonly occur in the adrenal glands and are called pheochromocytomas (PCC). PCC can cause excessive production of adrenal hormones, which can results in hypertension, headaches, anxiety, tachycardia, anxiety, and sweaty or clammy skin.

PGL and PCC are rare. They occur in an estimated 1 in 100,000 individuals per year, although the true incidence remains unclear. Most cases are sporadic, but approximately one-third are familial and due to an identifiable pathogenic variant in a disease-causing gene. Familial PGL/PCC can be non-syndromic; it can also be a feature of an underlying condition such as neurofibromatosis type 1, von Hippel-Lindau syndrome, or multiple endocrine neoplasia type 2. Paragangliomas are a feature of Carney-Stratakis syndrome, which is an autosomal dominant condition characterized by the development of paragangliomas and/or gastrointestinal stromal tumors (GIST).

The genes on this panel are associated with hereditary PGL/PCC, but the overall percentage of hereditary cancer cases caused by these risk factors is currently unclear. Inclusion of several PGL/PCC-related genes is expected to increase the clinical sensitivity of this test.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant can present differently, even among family members.

While the risks for paraganglioma and pheochromocytoma are currently unclear, it appears that malignancy associated with SDHA pathogenic variants is very rare.

For the SDHB gene, the risk of malignant paraganglioma is approximately 25%, the risk of renal cancer is 15%, and the risk of thyroid tumor development is approximately 2.5%. Pathogenic variants in this gene lead to metastatic disease in at least 40% of affected individuals.

While the risks for paraganglioma and pheochromocytoma are currently unclear, it appears that malignancy associated with SDHC pathogenic variants is very rare.

The risk of head and neck paragangliomas in individuals with pathogenic SDHD variants is estimated at 71%-79%. The risk of pheochromocytoma is 29%-53% by age 60. The risk of malignancy appears to be less than 5%.

While the risks for paragangliomas, particularly of the head and neck, are currently unclear, it appears that malignancy associated with SDHAF2 pathogenic variants is very rare.

Pheochromocytomas develop in 10%–20% of individuals with von Hippel-Lindau syndrome, and in 30%-50% of those cases, this is the first presenting clinical manifestation. Approximately 5% of these lesions become malignant.

The risk for pheochromocytoma is up to 13% in individuals with neurofibromatosis type 1 (NF1). The risk of malignancy in NF1-associated pheochromocytomas is more frequent (up to 12%) than in sporadic cases.

Head and neck paragangliomas and extra-adrenal abdominal paragangliomas are associated with pathogenic TMEM127 variants, but specific lifetime risks are currently uncertain. Affected individuals may present with either unilateral or bilateral pheochromocytomas with a mean age at diagnosis of 42 years. The risk of malignancy is approximately 1%.

The risk of pheochromocytoma in multiple endocrine neoplasia types 2A and 2B is 50%. These lesions are virtually always benign and have less than a 5% risk of malignancy.

The risk for malignant pheochromocytoma in individuals with a pathogenic MAX variant is approximately 25%.

Of all affected individuals with identifiable pathogenic variants, 90% will have a variant in NF1, RET, SDHB, SDHD, or VHL. The remainder will have an identifiable pathogenic variant in MAX, SDHA, SDHAF2, SDHC, or TMEM127.

PGL/PCC is inherited in an autosomal dominant pattern. Pathogenic variants in the genes SDHD, MAX, and SDHAF2 appear to only cause disease when paternally derived. Some cases of PGL/PCC are inherited from a parent while others are the result of a spontaneous de novo mutation. The rate of inherited versus de novo cases is currently unclear.

Testing for hereditary PGL/PCC may be considered in any individual with a personal and/or family history of:

  • paraganglioma and/or pheochromocytoma, particularly if early onset (<45 years)
  • multiple tumors, including bilateral adrenal pheochromocytoma
  • multifocal tumors with multiple synchronous or metachronous tumors
  • recurrent tumors
  • other clinical findings suggestive of an underlying syndrome, such as neurofibromatosis type 1, Carney-Stratakis, von Hippel-Lindau syndrome, or multiple endocrine neoplasia type 2 (MEN2)

  1. Bardella, C, et al. SDH mutations in cancer. Biochim. Biophys. Acta. 2011; 1807(11):1432-43. doi: 10.1016/j.bbabio.2011.07.003. PMID: 21771581
  2. Baysal, BE, Maher, ER. 15 years of paraganglioma: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations. Endocr. Relat. Cancer. 2015; 22(4):T71-82. doi: 10.1530/ERC-15-0226. PMID: 26113606
  3. Baysal, BE. Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 2002; 39(9):617-22. doi: 10.1136/jmg.39.9.617. PMID: 12205103
  4. Castro-Vega, LJ, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum. Mol. Genet. 2014; 23(9):2440-6. doi: 10.1093/hmg/ddt639. PMID: 24334767
  5. Clark, GR, et al. Germline FH mutations presenting with pheochromocytoma. J. Clin. Endocrinol. Metab. 2014; 99(10):E2046-50. doi: 10.1210/jc.2014-1659. PMID: 25004247
  6. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  7. Hoekstra, AS, et al. Models of parent-of-origin tumorigenesis in hereditary paraganglioma. Semin. Cell Dev. Biol. 2015; :None. doi: 10.1016/j.semcdb.2015.05.011. PMID: 26067997
  8. Kirmani, S, Young, WF. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2008 May 21. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301715
  9. Lenders, JW, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2014; 99(6):1915-42. doi: 10.1210/jc.2014-1498. PMID: 24893135
  10. Lodish, MB, Stratakis, CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract. Res. Clin. Endocrinol. Metab. 2010; 24(3):439-49. doi: 10.1016/j.beem.2010.02.002. PMID: 20833335
  11. Lonser, RR, et al. von Hippel-Lindau disease. Lancet. 2003; 361(9374):2059-67. doi: 10.1016/S0140-6736(03)13643-4. PMID: 12814730
  12. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  13. Papathomas, TG, et al. Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis. Eur. J. Endocrinol. 2014; 170(1):1-12. doi: 10.1530/EJE-13-0623. PMID: 24096523
  14. Santos, P, et al. Hereditary Pheochromocytoma. Int. J. Surg. Pathol. 2014; 22(5):393-400. doi: 10.1177/1066896914537683. PMID: 24903423
  15. UpToDate Online, Pheochromocytoma in genetic disorders. Accessed June 2015.

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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
EGLN1 NM_022051.2
FH NM_000143.3
KIF1B NM_015074.3
MAX NM_002382.4
MEN1 NM_130799.2
NF1 NM_000267.3
RET NM_020975.4
SDHA* NM_004168.3
SDHAF2 NM_017841.2
SDHB NM_003000.2
SDHC NM_003001.3
SDHD NM_003002.3
TMEM127 NM_017849.3
VHL NM_000551.3

SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.