Background A new paradigm in genetic panel testing for hereditary colorectal cancer (CRC) has emerged. CRC association with BRCA1/2 has been suggested, but guidelines do not include CRC in Hereditary Breast and Ovarian Cancer syndrome (HBOC).

Objectives We describe 6 patients with CRC and germline mutations in BRCA1 or BRCA2, detected by multi-gene panels, to highlight actionable findings that would have been missed by traditional CRC genetic testing.

Design/method 585 patients with a personal history of CRC and/or gastrointestinal (GI) polyps were tested. Variants were identified using an NGS-based cancer gene panel with CRC genes and BRCA1/2. Germline variants were classified using a point-based system based on ACMG guidelines. Clinical histories from test request forms were de-identified for analysis.

Results Hereditary cancer panel testing found Pathogenic (P) or Likely Pathogenic (LP) variants in 92 of 585 (15%) patients. Of the 92 mutation carriers, 69 (75%) had a P/LP variant in a CRC gene, while 6 (6%) had a P/LP variant in BRCA1/2. None of the patients with BRCA1/2 mutations reported Ashkenazi Jewish ancestry. The 4 male patients did not meet HBOC testing guidelines.

Conclusions In this series, a substantial minority of P/LP variants were in non-canonical CRC genes. BRCA1/2 pathogenic variants’ prevalence in the general population is insufficiently elevated to account for these findings. More research is needed to link CRC and BRCA1/2, and clinicians need to prepare themselves and their patients to deal with unexpected, potentially actionable.