This is part of a blog series from genetic counselors at the Basser Center. This was written by Derek Mann, MS.
One of the most important components of genetic testing to understand are the different types of results and exactly what they mean. Negative results, in particular, can be confusing to process.
To review, the purpose of genetic testing is to look for mutations, or variants, within specific genes, 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 could be needed for someone who is positive for, or is found to have, a variant in these genes. This could also identify what other family members should consider genetic testing.
While testing positive for a genetic mutation seems straightforward, testing negative can be more difficult to understand. What do we really learn when we don't find any variants or, in other words, the individual tests negative? Would someone who is negative always be clear of the increased cancer risks associated with gene mutations like BRCA? What if they have a family history of cancer? 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 following example:
- 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, or BRCA1 mutation, could explain 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 (though men can also pass gene mutations down to their children).
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 breast cancer (per the above example) 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 or mutation present in the genes tested. However, this also means the family history of cancer does not have a clear explanation. 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 yet detect. 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.
If you're considering genetic testing, this is why it's helpful to go through the process with the assistance of a genetic counselor. Genetic counselors can help you make sense of your family healthy history, process genetic testing results, and can suggest next steps.