Monthly Archives: June 2014

15 Years of Pheo Para Research


On April 25, 2014, Dr. Karel Pacak celebrated his 15th anniversary with the Pheochromocytoma/Paraganglioma Protocol at the National Institutes of Health in Bethesda, Maryland. Patients, friends, dignitaries, and colleagues past and present came together at the historic Cloisters building on this beautiful spring day to surprise the humble yet highly revered physician and researcher.

The intimate event included an informative history of pheochromocytoma, a brief presentation of available diagnostic and therapeutic radiological options, a delicious spread of Dr. Pacak’s favorite foods and dessert, and a heartfelt rendition of “Somewhere Over the Rainbow” sung by a talented young patient in Dr. Pacak’s honor. The resounding theme of the day’s events was just how respected and loved this clinician — a man who has dedicated his life to others — truly is!

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What is a VUS?


Variants of Uncertain Significance (VUS): Additional Testing, Meaning, & Management

by Melissa Gilstrap, MS, CGC

When my patients pursue genetic testing, I encourage them to think about the possible results as a Yes, No, or Maybe:

  • YES: POSITIVE- Deleterious (potentially harmful) mutation is detected and should be considered the cause of the pheochromocytoma or paraganglioma. Other family members can be tested for this mutation.
  • NO: NEGATIVE- No Mutation Detected. Causes of the individual’s pheo/para is still unknown and additional testing/research for other genetic causes may be indicated.
  • MAYBE: Variant of Uncertain Significance (VUS) detected. The VUS may or may not be the cause of the individual’s pheo/para and additional information is needed. Additional testing/research for other genetic causes may be indicated.

VUS results can be incredibly frustrating because patients are hoping to get straightforward YES/NO results. VUSs will likely be classified as either a deleterious mutation (YES) or a polymorphism/benign finding (NO) not leading to risk of pheo/para in the future. Additional information is needed in order to be able to better classify them. Once additional information is obtained and the VUS has been reclassified, most laboratories will notify the ordering provider so that the patient can be notified. Therefore, it is very important to stay in contact with the provider who orders genetic testing.

FAMILY STUDIES & OTHER TESTING: Most laboratories that find a VUS will offer to do family studies for free. This is where the lab offers to test “informative” family members for free for the VUS that was detected. “Informative” family members are individuals who it would be helpful to know if they had the VUS or not. For instance, let’s say an individual with a para is found to have a VUS. This individual also has an aunt on his mother’s side of the family with a pheo. The lab would likely offer to test the parents of the individual with the para and the maternal aunt to see if the VUS is tracking with the pheo/para in the family; or possibly from the father’s side and less likely to be the cause of the pheo/para in the family. These studies are typically free to enroll in but do take some effort on the part of the provider and patient to coordinate testing for family members.

Also, additional testing for other genes associated with pheo/para may be indicated. There are now large panel tests available that look at many genes at once; so if a provider only ordered SDHD testing, for instance, additional testing with a large panel may be an option.

Research studies are also available. There are many families out there who do not have a known genetic cause of the pheo/para in their family even though they have been tested for everything available. There are likely many additional genes that when mutated lead to pheo/para risk. Research studies can help find these additional genes. One of the studies I recommend to all individuals with pheo/para is the Cleveland Clinic SDH Study. Anyone with a pheo/para qualifies, even if a mutation or VUS has previously been detected. The goal of this study is to help clarify the pheo/para and other risks associated with SDHx genes but also to identify other genes associated with pheo/para. Free testing of the SDHx genes is conducted (if applicable) and the results are reported to the provider who enrolled the patient. Results typically take a year or more to get back and if a mutation or VUS is found, it must be verified through a clinical lab. Other genes are tested and if a mutation or VUS is found, the results are reported to the provider. This study requires enrollment by a healthcare provider who must fill out the study paperwork and report any results to the patient. People interested in this study should discuss it with their provider.


  • VUS, Likely polymorphism/benign: VUS has been found but there is significant evidence that the VUS is also found in the general population and not associated with increased risk for pheo/para. With just a little more evidence (possibly even a family study) the laboratory will feel comfortable calling the individual’s results “Negative.”
  • VUS, Little to no evidence or contradicting evidence regarding the meaning of the VUS; additional information needed to classify.
  • VUS, Likely deleterious mutation: VUS has been found and there is significant evidence that the VUS is likely to be a mutation leading to an increased risk for pheo/para. With just a little more evidence (possibly even a family study) the laboratory will feel comfortable calling the individual’s results “Positive.”

VUSs can have very different meanings depending on the gene the VUS was found in, the exact VUS found, and the personal/family history of the individual tested. For this reason, blanket statements about the meaning of VUS cannot be made and it is important to have a geneticist/genetic counselor involved in interpreting the meaning of the VUS for patients/families.

MANAGEMENT: Once a VUS is found, typically providers will pursue family studies, other testing, and possibly research studies. If the VUS is still the only genetic finding for a patient, management will vary again depending on the gene, exact variant, and personal/family history. Most patients with a “likely deleterious” VUS will be managed as though they have a mutation. Most patients with “likely polymorphism/benign” VUS will be managed as though a mutation was not detected. Again, blanket statements about the management for individuals with VUS cannot be made and it is important to have a geneticist/genetic counselor involved recommending management options for patients/families with VUSs.

HAVE QUESTIONS? Contact your provider or a geneticist/genetic counselor to discuss any genetic test results you have received and if any additional testing/research is indicated. In the US, a list of genetic counselors near you can be found by using the “Find a Counselor” function on