Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes.

PURPOSE

As panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes.

METHODS

A retrospective study of individuals with DPVs identified through a single testing laboratory from 2012 to 2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared with cancer histories of controls with a single PV matched by gene.

RESULTS

Among 644 individuals with DPVs, combinations that included the , , , , and genes occurred >10 times. There were 8883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with (43), compared with (47,  = .016) or (47,  = .015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the with single-gene controls. Individuals with 2 PVs also were younger at first cancer diagnosis (40) compared with single PV controls (47,  = .0038). This difference was not driven by age at first BC diagnosis among females.

CONCLUSION

Individuals with + or 2 PVs have a greater cancer burden than single gene controls. These findings can be used to counsel individuals with DPVs and their families and inform cancer screening recommendations.