Patients who watch crime shows think that DNA testing is as simple as taking a cheek swab and getting the results in two minutes so the case is solved at the end of the 42-minute episode. The reality? DNA can be identified from buccal cells in a cheek swab, but results take several weeks to obtain and are not always a simple negative or positive.

Helping patients understand the meaning of a negative result is not always straightforward and requires interpretation. A negative test result means that the laboratory did not find the specific variant that the test was designed to detect, but a true negative and a noninformative negative are different results.

True Negative Versus Noninformative Negative Genetic Findings

A true negative means that a pathogenic variant that has been identified in a patient’s family member (e.g., parent, sibling) has been ruled out in the tested individual. For example, when the child of a parent with a pathogenic variant in a colon cancer susceptibility gene such as MSH6 c.3939_3957dup tests negative for that specific pathogenic variant, the child has not inherited the known risk from the parent and has at least average risk for developing cancer depending on other personal and familial risk factors. A negative test does not mean a patient has no risk for developing cancer. Even when the genetic testing is negative, some individuals may still benefit from increased cancer surveillance.

A noninformative negative means that testing did not detect a pathogenic variant and the family has no known pathogenic variant. For this reason, genetics professionals strive to initiate testing in a family member who is most likely to provide informative results. Typically, it is someone with cancer diagnosis that suggests hereditary predisposition, especially if they are younger in age.

When testing is initiated in a family member who has a diagnosis of cancer or other features suggestive of hereditary risk and the result is negative, the noninformative result may be related to at least three possibilities:

  • A pathogenic variant could be present in one of the tested genes, but it cannot be detected by available methods. However, this is rare because of technologic advancements.
  • A pathogenic variant is present in the family but is not detectable with current multigene panel testing.
  • The family does not have a pathogenic variant.

Some families don’t have an individual with a diagnosis of cancer available for testing. If testing is done in a nonaffected individual and the result is negative, it can be related to any of the three previous possibilities, but it could also mean that the individual did not inherit a pathogenic variant that other relatives may have. Although that is considered a true negative, the family is informed that the presence of a pathogenic variant is unclear.

Patients with a noninformative negative should be managed based on their personal risk factors and family history. Involving a genetics professional to coordinate care and select the best person to initiate testing as well as facilitate accurate interpretation of the results will enable families to understand the true meaning and implications of a negative test result.