There are 3 possible test results in genetic testing: Positive, Negative, and Variant of Uncertain Clinical Significance (VUS)
Positive: A change or mutation in the gene is found that makes the gene non-functional. This means in most cases that the person HAS the increased cancer risk associated with the mutation.
Negative: No changes or mutations are found within the gene(s) assessed. A negative genetic test result typically significantly reduces – but does not completely rule out – the possibility of an underlying hereditary genetic cause for the cancer. If you receive a negative genetic testing result, this means that the cancer in you and/or your family is less likely to be due to a hereditary genetic cause. However, it still could be due to an inherited genetic mutation that our testing technology cannot yet detect or possible in a gene that was not tested. Your genetic counselor or other health care provider can help you interpret your negative test results in the setting of your other personal and family history to determine your residual cancer risks, if any.
Of note: A negative test result in the case of single site testing for a known familial mutation is usually a true negative result.
Variant of Uncertain Clinical Significance (VUS)
Sometimes, genetic testing can reveal a variant of uncertain clinical significance (VUS). A VUS is a change within the typical sequence of a gene, but whether or not this change causes problems with the functioning of the gene is unknown. VUSs typically are further stratified by the lab into several sub-categories that can vary by lab but typically include (in order from least likely to be deleterious to most likely): variant suspected benign > variant of uncertain significance > variant suspected deleterious > variant likely deleterious. A genetic change that the lab considers totally benign is usually called a “polymorphism”. Polymorphisms are fairly common and are not typically thought to cause any problems with the functioning of the gene or any clinical symptoms, therefore these genetic changes are usually not even included on the test report. VUSs will remain classified as such until the lab accumulates enough data where they can definitively call it a benign (polymorphism) or deleterious (cancer causing) change. Labs will obtain this data in many ways including reading through reports of that mutation in the literature, looking at functional studies to see how the gene should work, and evaluating their own internal data. It can take weeks to years to accumulate enough data where a lab can be comfortable definitively calling a variant. Many variants typically end up being downgraded to benign. VUSs are a fairly common finding during genetic testing, particularly in panel testing. When a VUS is detected during genetic testing, this usually has no implications on the clinical management of the patient. Clinical care decisions are not typically made based on VUSs and family members are usually not tested for these changes unless the change is a suspected deleterious VUS. If enough evidence is obtained that the VUS is upgraded to a suspected deleterious or deleterious variant then the provider should contact the patient with that information and their medical management should be altered to follow the current screening and management guidelines for that gene. Different providers and labs have different policies on how this will be done. Some providers will contact their patients directly when there has been a change to a VUS status while others place the responsibility on their patients to check back in on a regular basis to learn of updates to their VUS status. This is an important question to ask your ordering provider to ensure you obtain regular updated information on your genetic testing results if a VUS is found.
What are some potential pros and cons of genetic testing for hereditary cancer predisposition syndromes?
- Genetic testing may give you and your providers valuable information on cancer risks which can empower you to potentially remove or lower those risks through high risk surveillance and management
- Genetic testing may give you information regarding your family members’ cancer risks and allow them to take steps to remove or reduce their elevated risks for cancer, if present
- Genetic testing may give you and your family members peace of mind from knowing risks and being able to address them
- If there is a known mutation in the family and you are found to not have the mutation, you may feel a lot of relief
- Some people may experience anxiety from learning their exact lifetime cancer risks
- There is a real chance that you will receive test results with a variant of uncertain significance (VUS). The uncertainty of what this result means may cause some anxiety.
- Genetic information inherently involves your family. Finding out about a mutation in a hereditary cancer predisposition gene in yourself means that you learn that other family members could be at risk for that mutation, too. Some family members may not want to know that information and sometimes it can create friction within families.
- If a mutation is found, many people express a feeling of guilt for passing on a mutation to a child even though this is something that is out of their control.
- Technologies such as preimplantation genetic diagnosis (PGD) can help parents planning a pregnancy reduce the likelihood of passing on a genetic mutation to their child.
- Some family members who test negative for a familial mutation while other family members test positive experience a feeling of guilt for “dodging the bullet”. They may feel guilty for feeling relieved that they are not at increased risk while simultaneously having to watch a family member deal with their positive results and increased risk. These are all very normal and common reactions to have and there are many resources and support groups that can help address these issues.
- Potential insurance discrimination: as discussed on our section on insurance, there are federal laws in place that provide some protections for individuals who have tested positive for a genetic mutation. However, those changes do not apply to all forms of insurance. It is important to make sure that you have addressed with your health care provider how your testing may affect your insurance before proceeding with genetic testing.
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