The emerging significance of secondary germline testing in cancer genomics.

Many clinical laboratories now sequence the tumors from advanced cancer patients to identify oncogenic drivers and guide targeted therapies and clinical trials. One limitation of tumor sequencing is that it cannot distinguish between tumor-specific somatic (acquired) mutations and patients' germline (constitutional) variants. To definitively identify somatic variants, some clinical labs sequence both a normal sample from a patient and their tumor to subtract the germline variants from the somatic variants. Having a paired normal sample also allows for the identification of secondary germline mutations in cancer patients who may not meet the current clinical guidelines for genetic testing of cancer predisposition syndromes. Such simultaneous detection of somatic alterations and germline mutations during tumor-normal sequencing can guide therapeutic decision making for cancer patients and the identification and screening of at-risk family members. Here, we review the clinical workflow, advantages and disadvantages, and clinical utility of tumor-normal sequencing in the management of cancer patients.