Accurate risk assessment of developing cancer often includes genetic testing for germline mutations, which has clinical and treatment implications for the patient and his or her family members. When a mutation is detected, aggressive measures for cancer prevention and detection are often implemented. Depending on the gene or genes tested, a variable percentage of patients will receive a test report stating that a variant of unknown significance (VUS) has been detected. This means that a change in the genetic sequence has occurred, but whether the change is associated with an increased risk of cancer or another disease is unclear or unknown. The results are confusing and noninformative. Oncology nurses will undoubtedly encounter patients with a VUS; consequently, they need to understand the controversies and ambiguities that surround these test results.