The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in conferred substantial risks of BCC (OR, 8.0; = 1.9 × 10 ), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the locus were associated with BCC, suggesting as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, = 1.6 × 10 ) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene as a high-impact BCC predisposition gene and indicates that inactivation of by germline sequence variants may also lead to increased risk of cervical cancer.