Understanding a Negative Genetic Test Result
True Negative vs Uninformative Negative
One of the most important areas to understand about genetic testing is the types of results and what they mean. For today’s post, I will focus specifically on what information we can learn from a negative result.
To review, genetic testing is looking for mutations, or variants, which are like spelling mistakes within our DNA. An example of this would be looking for variants within the genes BRCA1 and BRCA2 in an individual with a family history of breast and/or ovarian cancer. By identifying these variants, we can learn what screening or management would be needed for someone who is positive for, or is found to have, a variant in these genes, as well as who else in the family may be at risk for inheriting the identified variant.
However, what do we learn when we do not find any variants within this testing, or the individual tests negative? Would someone who is negative always be clear of these increased risks, even with a family history of cancer? The answer to this will be explained in more detail below, but in general, this depends on the information we have about the family history. With this information, we can determine whether a negative result is a “true negative” or an “uninformative negative”
To explain the difference between a true negative and an uninformative negative, let’s use the example below:
An individual is pursuing genetic testing due to a family history of breast cancer affecting her mother, maternal aunt, and maternal grandmother.
For a true negative to occur, we would need to have a known variant in the family that we can test for. In this example, let’s say that the individual’s mother and maternal aunt had previously undergone genetic testing revealing the same variant in the BRCA1 gene. This variant would be explaining the family history of breast cancer, and provides us with the specific variant to test for in the individual. By looking for this specific variant, we can either confirm or deny that the individual inherited the variant from her mother. If the specific variant is not identified, this is a true negative result. This result would indicate that the patient did not inherit the variant causing the family history of cancer, and is therefore not at an increased risk for these cancers. We would then say that the patient’s chance for developing cancer is now lowered to the general population risk, and would be able to follow general population screening and management guidelines.
With an uninformative negative, the individual would present with the same family history, but no previous genetic testing results. In this case, testing could be completed for a group, or panel, of genes associated with breast cancer. If the individual were to test negative, it is reassuring that there is not a variant present in the genes tested. However, as there is still the family history of cancer that is not explained. This is referred to as an uninformative negative. Due to limitations in genetic testing technology, as well as limitations in what testing can reveal with our current knowledge of these genes, it is still possible that there is a variant present that we cannot detect currently. In these situations, the individual’s screening and management would remain based on the family history, as an increased risk cannot be ruled out.
An uninformative negative is not a permanent result. An uninformative negative can be changed to a true negative if a variant explaining the family history is found. For example, if this individual’s mother, aunt or grandmother were to pursue genetic testing and a variant in BRCA1 was identified that would have been detected on the individual’s negative testing, then that uninformative negative would change to a true negative.
Editor: Derek Mann, MS, LCGC is a licensed certified genetic counselor within the Cancer Risk Evaluation Program at the University of Pennsylvania and is a medical advisor for HIS Breast Cancer Awareness