Both germline and somatic mutations contribute to tumor pathogenesis. The integration of genetic and genomic sequencing into cancer care has unveiled the presence of unique mutations that characterize tumors based on their molecular origins.1 In some cases, specific molecularly targeted therapies may be incorporated into a personalized treatment plan based on the presence of a particular mutation biomarker.2–5
Germline variants are inherited and are present in all cells in the body. Health care providers may recommend genetic testing for germline mutations associated with a hereditary cancer syndrome based on a patient’s family history of cancer, if they are diagnosed with particular types of cancer, and/or if they are diagnosed at an early age. Patients may also learn about familial germline mutations associated with cancer syndromes if someone in their family has received clinical genetic testing (gene panel, exome, genome) for a pediatric presentation of a rare genetic condition. People may also learn about germline mutations through direct-to-consumer (no interface with an ordering physician) or direct-to-provider testing (interface with a physician contracted with the lab).6,7
If a patient is found to carry a germline mutation associated with a hereditary cancer syndrome, these findings have implications for the patient and their family. First-degree relatives may have up to a 50% chance of having the same mutation, even if they do not present with cancer. Each mutation may confer risk for many different types of cancers, many of which have specific high-risk screening and management guidelines. With confirmation of a germline variant, risk management plans are tailored to patients beyond standard public health guidance regarding commencing cancer risk screening on the basis of one’s age or sex or moderating health behaviors such as increasing exercise or quitting smoking.8
Somatic mutations are acquired in individual cells throughout a person’s lifetime and make up the majority of mutations identified in tumor samples. In the context of molecular tumor testing for patients with a cancer diagnosis, somatic mutations are confined to tumor tissue. These mutations may be identified through tumor sequencing, which may or may not include a comparison to the germline (see Clinical Vignette No. 1). While both germline and somatic mutations may inform treatment and management options, there are no hereditary implications of purely somatic mutations. However, germline mutations may provide predictive information to an individual and their family about hereditary disease risk. If a mutation originally identified from a tumor sample is confirmed in the germline, the patient and their family may have a higher risk for cancer recurrence, additional cancers, or other diseases.9–11 Currently, the National Comprehensive Cancer Network (NCCN) criteria recommend germline testing through a Clinical Laboratory Improvement Amendments (CLIA)–approved lab for any genes for which a patient meets criteria based on clinical and/or family history, because tumor sequencing is not ...