Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories.

Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016. The majority of individuals (92.8%) met testing criteria for Hereditary Breast and Ovarian Cancer (HBOC) and/or Lynch syndrome (LS). Overall, 17,340 PVs were identified in 17,000 (6.7%) of the tested individuals. The PV positive rate was 9.8% among individuals with a personal cancer history, compared to 4.7% in unaffected individuals. PVs were most common in BRCA1/2 (42.2%), other breast cancer (BR) genes (32.9%), and the LS genes (13.2%). Half the PVs identified among individuals who met only HBOC testing criteria were in genes other than BRCA1/2. Similarly, half of PVs identified in individuals who met only LS testing criteria were in non-LS genes. These findings suggest that genetic testing with a pan-cancer panel in this cohort provides improved clinical utility over traditional single-gene or single-syndrome testing.