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Guest Blog: Genetic Variants of Uncertain Significance

October 25, 2016


ledbetter-headshotby Nancy Ledbetter

Early on in my genetics nursing career, I remember explaining the possibility of a variant of uncertain significance (VUS) to a patient, who laughed and said, “Variant of uncertain significance? That sounds like something out of Monty Python!” I had to admit she had a good point. It sounds like a ridiculous outcome for such a serious endeavor as genetic testing for cancer risk, but is an outcome many must face when undergoing genetic testing.

When the laboratory report states a VUS has been detected, it means that the tested gene is different in some way, compared to the same gene in the vast majority of other people. The important question is: Does the variant affect the function of the gene?

BRCA1 and BRCA2 genes, and most other genes associated with breast cancer risk, are tumor suppressor genes. When they are functioning properly, they contribute to the body’s ability to avoid cancer. When there is a deleterious, or pathogenic variant (aka mutation), the gene’s function is impaired, and malignant tumors are likely to develop. However, the vast majority of VUS’s are benign variants that do not affect the function of the gene, and are therefore not harmful.

VUS’s are always a possibility with genetic testing for hereditary cancer syndromes. The fact is, we are all just as different individually on the inside as we are on the outside. Back when BRCA1/BRCA2 testing was new, the rate of VUS’s was more than 10%, which is much higher than today. Over the years the VUS rate of the BRCA genes decreased to about 2-4% (the rate varies depending on the lab) as data were compiled and the VUS’s were reclassified.

The expectation was that the rate of VUS’s would continue to decrease, but then panel testing came along. Just adding genes to a test will increase the rate of VUS, but many tests that are performed today are done on genes that have not been studied as much as BRCA1/BRCA2, so the likelihood of VUS on those genes is much higher than for BRCA1 and BRCA2.

In most cases, a VUS is not used to determine medical interventions. Because most VUS’s are benign, the clinician uses the patient’s history and family history to determine the appropriate interventions. And, it is usually not advisable for relatives who have not had cancer to have testing for a VUS, as it is not a reliable guide to their cancer risk estimation.

It can be helpful for relatives with a history of cancer to have testing for a VUS to help reclassify a VUS. If a family has multiple members with breast cancer, but only some of them have a VUS, then the VUS is unlikely to be the driver of their hereditary risk. Many labs have programs in which relatives with cancer, and sometimes other relatives, can participate in VUS testing efforts to help reclassify a VUS.

People who have had a VUS finding on a test, especially if it was performed many years ago, may be notified if their VUS is reclassified, but this does not happen consistently. There are a couple of ways a patient can find out if their VUS has been reclassified. One is to check with the health care provider who ordered the genetic test. (Their name is on the test report.) The other is to call the lab directly that performed the test and ask them if their VUS has been reclassified.

Nancy Ledbetter, RN, CNS, APNG, AOCNS is an oncology clinical nurse specialist with certification in both genetics and oncology.  She has been providing hereditary cancer risk assessment, including genetic counseling and testing services since 2000. Prior to that, she gained extensive cancer nursing experience in the medical oncology, bone marrow transplant, and radiation oncology settings.   She recently opened her private practice in Portland, Oregon. Check out her website at www.cancerriskrn.com.

Related Resources

FORCE Information: Inherited Mutations and Cancer

FORCE Information: Should I Get Genetic Testing?

FORCE Information: Finding a Genetics Specialist

FORCE Helpline: Speak with a Board-Certified Genetic Counselor 

FORCE Blog: Regulating the Next Generation of Genetic Tests

FORCE XRAYS: Genetic testing for cancer risk: How many genes to sequence?

FORCE XRAYS: New York Times report demonstrates need for genetic counseling, but doesn’t give the whole story

Joining FORCEs Newsletter: New Tools Help with Uncertain or Negative BRCA Results

FindMyVariant: FindMyVariant is testing a website for individuals with variants of uncertain significance who want to connect with their relatives and find more about their variant

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