Cascade testing for hereditary cancer using multigene panels

Current guideline recommend single gene/variant testing in relatives of patients with known pathogenic or likely pathogenic variants (PGVs) in cancer predispostion genes. This approach may preclude the use of risk-reducing strategies in family members who had PGVs in other cancer predisposition genes. A study of cascade testing (3,696 relatives of 7,433 probands) using multigene panels found unexpected PGVs in 230 relatives (6.2%), including 144 who were negative for the familial PGV but positive for a PGV in a different gene than the proband, and 74 who tested positive for the familial PGV and had an additional PGV in a different gene than the proband. Among the relatives with unexpected PGVs, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the famial PGV would have resulted in missed, actionable findings for a subset of relatives.