ATM c.7374_7375insAlu is a French-Canadian founder pathogenic variant associated with predisposition to pancreatic and breast cancer.

Founder pathogenic variants (PVs) in BRCA1, BRCA2 and PALB2 increase lifetime risk of developing breast (BC), ovarian (OC) and pancreatic (PC) cancer. They have been identified in French-Canadians (FC), a population exhibiting genetic drift due to common ancestral origins. PVs in ATM also increase BC and PC risk; however, ATM founder PVs have not been described in FCs. Here, we report the identification of a germline ATM c.7374_7375insAlu in a FC family with BC and PC. Using a case-control study of 19 852 FC individuals, we show that heterozygous carriers of this variant are more prevalent in PC cases versus controls (6/325 (1.85%) vs 28/18 129 (0.15%), p<0.001) and BC cases versus female controls (5/858 (0.58%) vs 13/9768 (0.13%), p<0.001). There was no difference in the prevalence of heterozygous carriers in patients with endometrial cancer or OC compared to controls. ATMc.7374_7375insAlu carriers share a common haplotype, suggesting that the variant was inherited from a common FC ancestor, which originated approximately 10.53 generations (305 years) ago. Taken together, this study identifies ATM c.7374_7375insAlu as a novel FC founder PV that contributes to PC and BC predisposition. Improving carrier detection may identify at-risk relatives who may benefit from cancer-directed surveillance.