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  • Test code: 01302
  • 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
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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)

MAX NF1 RET SDHA SDHAF2 SDHB SDHC SDHD TMEM127 VHL

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.

EGLN1 FH KIF1B MEN1

  • 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.

SDHA
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.

SDHB
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.

SDHC
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.

SDHD
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.

SDHAF2
Pathogenic variants appear to be rare, highly penetrant, and are associated with HNPs with a low risk of malignancy.

VHL
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.

NF1
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.

TMEM127
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.

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

MAX
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)
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  2. 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
  3. 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
  4. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  5. 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
  6. 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
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  11. 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
  12. 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
  13. Baysal, BE. Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 2002; 39(9):617-22. doi: 10.1136/jmg.39.9.617. PMID: 12205103
  14. Lonser, RR, et al. von Hippel-Lindau disease. Lancet. 2003; 361(9374):2059-67. doi: 10.1016/S0140-6736(03)13643-4. PMID: 12814730
  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. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
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  29. 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
  30. 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
  31. 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
  32. Ni, Y, et al. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum. Mol. Genet. 2012; 21(2):300-10. doi: 10.1093/hmg/ddr459. PMID: 21979946
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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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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

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