• Test code: 01302
  • 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

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. Many of these genes are also associated with an increased risk of gastrointestinal stromal tumors (GIST) as well as other cancer types.

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)


Add-on Preliminary-evidence Genes for Hereditary Paraganglioma-Pheochromocytoma (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 may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial.

While the risks for paraganglioma and pheochromocytoma are currently unclear, it appears that malignancy associated with SDHA pathogenic variants is rare. There is an increased risk of GIST, and preliminary evidence suggests there may also be an increased risk of renal cancer.

For the SDHB gene, the risk of malignant paraganglioma is approximately 25%, and the risk of renal cancer is 15%. Pathogenic variants in this gene lead to metastatic disease in approximately 40% of affected individuals. There is an increased risk of GIST and preliminary evidence to suggest pathogenic variants in SDHB may be associated with breast and thyroid cancers.

While the risks for paraganglioma and pheochromocytoma are currently unclear, it appears that malignancy associated with SDHC pathogenic variants is rare. There is also an increased risk of GIST and renal cancer associated with SDHC.

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%. There is preliminary evidence to suggest pathogenic variants in SDHD are associated with an increased risk of breast, thyroid and renal cancers.

Pathogenic variants appear to be rare, highly penetrant, and are associated with HNPs with a low risk of malignancy.

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%) compared to sporadic cases.

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. The risk of malignancy appears to be low.

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

Hereditary PCCs and/or PGLs due to pathogenic variants in MAX are infrequent, and are often observed in individuals with a positive family history. There appears to be a tendency toward bilateral or multiple tumors within the same gland. It is unclear if there is a risk of malignancy.

Of all affected individuals with identifiable pathogenic variants, 90% will have a variant in NF1, RET, SDHB, SDHD, or VHL. Approximately 10% will have an identifiable pathogenic variant in MAX, SDHA, SDHAF2, SDHC, or TMEM127.

The genes associated with PGL/PCC are inherited in an autosomal dominant pattern. There is evidence to suggest a parent-of-origin effect for the SDHD gene and possibly others. 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. SDHA and SDHB are also associated with autosomal recessive mitochondrial complex II deficiency.

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)

There are also some common, general features suggestive of a hereditary cancer syndrome family. These include:

  • cancer diagnosed at an unusually young age
  • different types of cancer that have occurred independently in the same person
  • cancer that has developed in both organs of a set of paired organs (e.g., both kidneys)
  • several close blood relatives that have the same type of cancer
  • unusual cases of a specific cancer type (e.g., breast cancer in a man)
  1. Pasini, B, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur. J. Hum. Genet. 2008; 16(1):79-88. doi: 10.1038/sj.ejhg.5201904. PMID: 17667967
  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. Santos, P, et al. Hereditary Pheochromocytoma. Int. J. Surg. Pathol. 2014; 22(5):393-400. doi: 10.1177/1066896914537683. PMID: 24903423
  4. 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
  5. 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: http://www.ncbi.nlm.nih.gov/books/NBK1548/ PMID: 20301715
  6. 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
  7. 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
  8. 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
  9. Baysal, BE. Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 2002; 39(9):617-22. doi: 10.1136/jmg.39.9.617. PMID: 12205103
  10. Lonser, RR, et al. von Hippel-Lindau disease. Lancet. 2003; 361(9374):2059-67. doi: 10.1016/S0140-6736(03)13643-4. PMID: 12814730
  11. Italiano, A, et al. SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. BMC Cancer. 2012; 12:408. doi: 10.1186/1471-2407-12-408. PMID: 22974104
  12. UpToDate Online, Pheochromocytoma in genetic disorders. http://www.uptodate.com/contents/pheochromocytoma-in-genetic-disorders Accessed August 2018.
  13. Melmed, S, et al. Williams Textbook of Endocrinology. 12 ed. Philadelphia, PA: Saunders Elsevier Inc; 2011:545-80.
  14. Dwight, T, et al. Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am. J. Surg. Pathol. 2013; 37(2):226-33. doi: 10.1097/PAS.0b013e3182671155. PMID: 23060355
  15. Pantaleo, MA, et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J. Natl. Cancer Inst. 2011; 103(12):983-7. PMID: 21505157
  16. Ricketts, CJ, et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J. Urol. 2012; 188(6):2063-71. PMID: 23083876
  17. Gimenez-Roqueplo, AP, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003; 63(17):5615-21. PMID: 14500403
  18. Ricketts, CJ, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum. Mutat. 2010; 31(1):41-51. PMID: 19802898
  19. Ni, Y, et al. Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. Endocr. Relat. Cancer. 2015; 22(2):121-30. PMID: 25694510
  20. Lefebvre, M, Foulkes, WD. Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol. 2014; 21(1):e8-e17. PMID: 24523625
  21. Favier, J, et al. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015; 11(2):101-11. PMID: 25385035
  22. Costa, MH, et al. Pheochromocytomas and Paragangliomas: Clinical and Genetic Approaches. Front Endocrinol (Lausanne). 2015; 6:126. PMID: 26347711
  23. Burnichon, N, et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin. Cancer Res. 2012; 18(10):2828-37. PMID: 22452945
  24. Baysal, BE. Genomic imprinting and environment in hereditary paraganglioma. Am J Med Genet C Semin Med Genet. 2004; 129C(1):85-90. PMID: 15264276
  25. Bayley, JP, et al. Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations. BMC Med. Genet. 2014; 15:111. PMID: 25300370
  26. Yeap, PM, et al. Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect. J. Clin. Endocrinol. Metab. 2011; 96(12):E2009-13. PMID: 21937622
  27. Korpershoek, E, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J. Clin. Endocrinol. Metab. 2011; 96(9):E1472-6. PMID: 21752896
  28. Buffet, A, et al. A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. Horm. Metab. Res. 2012; 44(5):359-66. PMID: 22517557
  29. Jiang, Q, et al. A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma. Int J Clin Exp Pathol. 2015; 8(10):12188-97. PMID: 26722403
  30. Williamson, SR, et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod. Pathol. 2015; 28(1):80-94. PMID: 25034258
  31. Schiavi, F, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005; 294(16):2057-63. PMID: 16249420
  32. Peczkowska, M, et al. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab. 2008; 4(2):111-5. PMID: 18212813
  33. Neumann, HP, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004; 292(8):943-51. PMID: 15328326
  34. Burnichon, N, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 2010; 19(15):3011-20. doi: 10.1093/hmg/ddq206. PMID: 20484225
  35. Miettinen, M, Lasota, J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int. J. Biochem. Cell Biol. 2014; 53:514-9. doi: 10.1016/j.biocel.2014.05.033. PMID: 24886695
  36. 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
  37. 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
  38. Ricketts, C, et al. Germline SDHB mutations and familial renal cell carcinoma. J. Natl. Cancer Inst. 2008; 100(17):1260-2. doi: 10.1093/jnci/djn254. PMID: 18728283
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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
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

EGLN1: Sequencing analysis for exons 5 includes only cds +/- 10 bp.
FH: Sequencing analysis for exons 9 includes only cds +/- 10 bp.
KIF1B: Sequencing analysis for exons 20, 30 includes only cds +/- 10 bp.
MAX: Sequencing analysis for exons 2 includes only cds +/- 10 bp.
MEN1: Sequencing analysis for exons 2 includes only cds +/- 10 bp.
NF1: Sequencing analysis for exons 2, 7, 25, 41, 48 includes only cds +/- 10 bp.
SDHA: Deletion/duplication analysis is not offered for this gene and sequencing analysis is not offered for exon 14. Sequencing analysis for exons 6-8 includes only cds +/- 10 bp.
SDHC: Sequencing analysis for exons 2, 6 includes only cds +/- 10 bp.