<h4>Purpose</h4>To evaluate cancer risk, age-specific penetrance, and mortality associated with heterozygous pathogenic or likely pathogenic (P/LP) germline <i>PALB2</i> variants identified through genomic ascertainment and to assess modification by family history of cancer.<h4>Patients and methods</h4>We conducted a case-control study in two large population-based adult cohorts: the UK Biobank (n=469,580) and Geisinger MyCode (n=167,050). Here, PALB2 is linked to cancer.