Fig. 1: Family, sample description, and study pipeline.

A Family pedigree. Individuals diagnosed with cancer are marked in black, and with polyps, in gray. The tumor types and number of polyps are indicated below the corresponding individual symbol. Detailed tumor phenotypes and ages at diagnosis are shown in Supplementary Table S1. Blue rectangles mark the individuals from whom skin biopsies were obtained for the culture of single-cell fibroblast colonies. Filled blue rectangles depict the individuals whose single-cell fibroblast colonies were used for the mutation accumulation experiments. The violet rectangle highlights the individual with a sequenced tumor sample. Sequenced sub-families are framed by rectangles made with dashed orange lines, where individual IDs are detailed for the sequenced individuals. Plus and minus signs mark the POLD1 L474P carrier status, and a plus sign between parentheses (+) indicates an obligate carrier. B Experimental workflow performed on immortalized fibroblasts from family members for the assessment of somatic mutation accumulation. C Algorithm used for calling somatic mutations accumulated during cell line growth. D Algorithm used for calling germline de novo mutations.