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Paraganglioma-Pheochromocytoma Comprehensive Panel

Diseases Targeted:

Hereditary Pheochromocytoma
Hereditary Paraganglioma

Overview:

The Pheochromocytoma or Paraganglioma Comprehensive Panel examines 11 genes associated with an increased risk for pheochromocytoma or paraganglioma. This test includes both well-established pheochromocytoma or paraganglioma susceptibility genes, as well as candidate genes with limited evidence of an association.

Who is this test for?

Patients with a personal or family history suggestive of hereditary pheochromocytoma or paraganglioma. Red flags for hereditary cancer could include onset of cancer prior to the age of 50 years, more than one primary cancer in a single person, and multiple affected people within a family. The presence of more than one pheochromocytoma or paraganglioma in first or second degree relatives, as well as the presence of renal cell carcinoma or gastrointestinal stromal tumors in a patient’s clinical or family history indicate that genetic testing for a hereditary pheochromocytoma or paraganglioma syndrome may be warranted. After consideration of a patient’s clinical and family history, this testing may be appropriate for some pediatric patients as preventative steps may be warranted in childhood. (If there are specific genes that you do NOT want included, please indicate this on the test requisition form.) This test is designed to detect individuals with a germline pathogenic variant, and is not validated to detect mosaicism below the level of 20%. It should not be ordered on tumor tissue.

What are the potential benefits for my patient?

Patients identified with a hereditary pheochromocytoma or paraganglioma can benefit from increased surveillance and preventative steps to better manage their risk for cancer. Additionally, there are strong genotype/phenotype correlations known for many of the genes that can cause these types of tumors. Some genes are correlated with a high risk for malignant transformation, while others are not, potentially guiding treatment towards less aggressive interventions. Some genes are associated with other malignancies, and additional screening is needed. Also, if an inherited susceptibility is found, your patient’s family members can be tested to help define their risk. If a pathogenic variant is identified in your patient, close relatives (children, siblings, parents) could have as high as a 50% risk to also be at increased risk. In some cases, screening should begin in childhood.

Order Options

Sequencing (included)
Del/Dup (included)

 

Genes

FH, MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL ( 11 genes )

Coverage:

99% at 50x

Specimen Requirements:

Blood (two 4ml EDTA tubes, lavender top) or Extracted DNA (3ug in EB buffer) or Buccal Swab or Saliva (kits available upon request)

Test Limitations:

Test results and variant interpretation are based on the proper identification of the submitted specimen and use of correct human reference sequences at the queried loci. In very rare instances, errors may result due to mix-up or co-mingling of specimens. Positive results do not imply that there are no other contributions, genetic or otherwise, to the patient's phenotype, and negative results do not rule out a genetic cause for the indication for testing. Result interpretation is based on the collected information and Alamut annotation available at the time of reporting. This assay is not designed or validated for the detection of mosaicism. DNA alterations in regulatory regions or deep intronic regions (greater than 20bp from an exon) will not be detected by this test. There are technical limitations on the ability of DNA sequencing to detect small insertions and deletions. Our laboratory uses a sensitive detection algorithm, however these types of alterations are not detected as reliably as single nucleotide variants. Rarely, due to systematic chemical, computational, or human error, DNA variants may be missed. Although next generation sequencing technologies and our bioinformatics analysis significantly reduce the confounding contribution of pseudogene sequences or other highly-homologous sequences, sometimes these may still interfere with the technical ability of the assay to identify pathogenic variant alleles in both sequencing and deletion/duplication analyses. Deletion/duplication analysis can identify alterations of genomic regions which are a single exon in size. When novel DNA duplications are identified, it is not possible to discern the genomic location or orientation of the duplicated segment, hence the effect of the duplication cannot be predicted. Where deletions are detected, it is not always possible to determine whether the predicted product will remain in-frame or not. Unless otherwise indicated, in regions that have been sequenced by Sanger, deletion/duplication analysis has not been performed.

Patients with Bone Marrow Transplants:
DNA extracted from cultured fibroblasts should be submitted instead of blood/saliva/buccal samples from individuals who have undergone allogeneic bone marrow transplant and from patients with hematologic malignancy.

CPT Codes:

CPT Code 81403, 81404, 81405, 81406, 81479

NOTE: The CPT codes listed on the website are in accordance with Current Procedural Terminology, a publication of the American Medical Association. CPT codes are provided here for the convenience of our clients. Clients who bill for services should make the final decision on which codes to use.

Gene Descriptions:

Gene Reason Reference
FH Heterozygous germline pathogenic variants in FH are associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). The evidence for an association between HLRCC and paragangliomas or pheochromocytomas is contradictory, and additional research is needed. PubMed: 20301715; OMIM: 136850
MAX Autosomal dominant pathogenic variants in the MAX gene have been associated with susceptibility to pheochromocytoma and paraganglioma. Risk for the development of a pheochromocytoma in individuals with germline MAX pathogenic variants is much higher if the variant was paternally inherited. PubMed: 20301715; OMIM: 154950
NF1 Autosomal dominant pathogenic variants in NF1 cause Neurofibromatosis Type 1, which is associated with several types of benign tumors and cancer, including pheochromocytomas. PubMed: 17636453, 20301288, 9639526, 27787920; OMIM: 613113
RET Autosomal dominant pathogenic variants in the RET gene are associatediwth Multiple endocrine neoplasia type 2 (MEN 2), which is associated with medulary thyroid carcinoma, pheochromocytoma, and other clinical findings. PubMed: 20301434; OMIM: 164761
SDHA Autosomal dominant pathogenic variants in SDHA are one genetic cause of Hereditary Paragangliomas-Pheochromocytoma Syndromes (HPPS), and are responsible for approximately .6-3% of cases PubMed: 20301715, 26273102
SDHB Autosomal dominant pathogenic variants in SDHB are one genetic cause of Hereditary Paraganglioma-Pheochromocytoma syndrome (HPPS) and are responsible for approximately 22-38% of cases. They are also associated with Carney-Stratakis syndrome, which is characterized by the presence of paragangliomas and gastrointestinal stromal tumors. SDHB-related HPPS has the highest risk for malignancy in comparison to the different genetic causes of the condition. PubMed: 20301715, 26273102; OMIM: 606864
SDHC Heterozygous pathogenic variants in the SDHC gene are responsible for between 4 and 8% of cases of Hereditary Parganglioma-Pheochromocytoma syndrome (HPPS). PubMed: 20301715; OMIM: 602413
SDHD Autosomal dominant pathogenic variants in the SDHC gene are the most common cause of Hereditary Parganglioma-Pheochromocytoma syndrome (HPPS). Of note, tumor development occurs much more frequently when the pathogenic variant is inherited from the father (paternal origin). PubMed: 20301715; OMIM: 602690
VHL Heterozygous pathogenic variants in VHL cause von Hippel-Lindau (VHL) syndrome, which increases the risk for many types of cancer, including pheochromocytoma, hemangioblastoma, clear cell renal cell carcinoma, and neuroendocrine tumors. PubMed: 20301636, 27114602, 25834951, 24355456
SDHAF2 Autosomal dominant pathogenic variants in the SDHAF2 gene have been associated with susceptibility to paragangliomas. Risk for developing a paraganglioma in individuals with germline SDHAF2 pathogenic variants is much higher if the variant was paternally inherited, and they most frequently occur in the skull base and neck. PubMed: 20301715; OMIM: 613019
TMEM127 Heterozygous pathogenic variants in the SDHC gene are associated with an increased risk for pheochromocytomas. PubMed: 20301715; OMIM: 613403
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