It is estimated that up to 10% of cancer incidents are attributed to inherited genetic alterations. Despite extensive research, there are still gaps in our understanding of genetic predisposition to cancer. It was theorized that ultra-rare variants partially account for the missing heritable component. We harness the UK BioBank dataset of ~ 500,000 individuals, 14% of which were diagnosed with cancer, to detect ultra-rare, possibly high-penetrance cancer predisposition variants. We report on 115 cancer-exclusive ultra-rare variations and nominate 26 variants with additional independent evidence as cancer predisposition variants. We conclude that population cohorts are valuable source for expanding the collection of novel cancer predisposition genes.
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