Cascade testing for hereditary cancer: comprehensive multigene panels identify unexpected actionable findings in relatives

Current guidelines recommend single variant testing in relatives of patients with known pathogenic or likely pathogenic germline variants in cancer predisposition genes. This approach may preclude the use of risk-reducing strategies in family members who have pathogenic or likely pathogenic germline variants in other cancer predisposition genes. Cascade testing using multigene panels was performed in 3696 relatives of 7433 probands. Unexpected pathogenic or likely pathogenic germline variants were identified in 230 (6.2%) relatives, including 144 who were negative for the familial pathogenic or likely pathogenic variant but positive for a pathogenic or likely pathogenic variant in a different gene than the proband and 74 who tested positive for the familial pathogenic or likely pathogenic variant and had an additional pathogenic or likely pathogenic variant in a different gene than the proband. Of the relatives with unexpected pathogenic or likely pathogenic germline variants, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the familial pathogenic or likely pathogenic variant would have resulted in missed, actionable findings for a subset of relatives.

Automated summary

Current guidelines recommend single variant testing in relatives of cancer patients with known pathogenic or likely pathogenic germline variants. However, this approach may result in missed risk-reducing strategies in family members with pathogenic or likely pathogenic variants in other cancer predisposition genes. Cascade testing using multigene panels identified unexpected pathogenic or likely pathogenic germline variants in 6.2% of relatives, including those who were negative for the familial variant but positive for a variant in a different gene, as well as those who tested positive for the familial variant and had an additional variant in a different gene.