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

Founder pathogenic variants (PVs) in , and 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 also increase BC and PC risk; however, founder PVs have not been described in FCs. Here, we report the identification of a germline 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. c.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 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.