Germline variants in Ribosomal Protein S20 (RPS20) have been reported to predispose to colorectal cancer (CRC) based on occurrence in a total of 3455 CRC cases and co-segregation with disease in 3 families. RPS20 encodes a component of the ribosomal 40 S subunit, but the mechanism by which the variants might influence CRC risk remains unclear. The current study assessed the association of RPS20 variants with CRC predisposition in whole-genome sequencing (WGS) data from 9738 CRC cases and 161,403 cancer-free controls from the COloRectal tumour Gene Identification consortium (CORGI) study, 100,000 Genomes (100kGP) and UK Biobank (UKB). One hundred and sixty-eight CORGI cases and 23 100kGP cases were recruited based on a family history of CRC. After excluding common polymorphisms, we identified one putative loss-of-function RPS20 variant in cases (p.Ile89fs), and none in controls. This individual was not from a multiplex family, and hence co-segregation analysis of the variant and disease was not possible. One in-frame deletion and one missense variant predicted to be probably pathogenic were found in controls. We also reviewed the evidence on RPS20 and CRC risk from the literature. We concluded that the combined data do not show conclusively that RPS20 is a proven CRC predisposition gene. Its inclusion in diagnostic gene panels for CRC cannot be justified until and unless stronger supporting evidence becomes available in the future.