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, though 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 2012-2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared to cancer histories of controls with a single PV matched by gene. Results Among 644 individuals with DPVs, combinations that included the ATM, BRCA1, BRCA2, CHEK2 and PALB2 genes occurred >10 times. There were 8,883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with ATM+CHEK2 (43), compared to ATM (47, P=.016) or CHEK2 (47, P=.015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the ATM+CHEK2 vs. single gene controls. Individuals with two CHEK2 PVs also were younger at first cancer diagnosis (40) compared to single CHEK2 PV controls (47, P=.0038). This difference was not driven by age at first BC diagnosis among females. Conclusion Individuals with ATM+CHEK2 or two CHEK2 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.