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Germline mutations in DNA polymerase ɛ ( POLE ) and δ ( POLD1 ) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried  POLE  c.1270C&gt;G (p.Leu424Val) or  POLD1  c.1433G&gt;A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons.  POLE  p.L424V was identified in a 28-year-old polyposis and CRC patient, as a  de novo  mutation. None of the 858 cases studied carried  POLD1  p.S478N. A new mutation,  POLD1  c.1421T&gt;C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family,  in silico  predictions, and previously published yeast assays.  POLE  and  POLD1  mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of  POLE  and  POLD1  should be considered in routine genetic diagnostics. Until additional evidence is gathered,  POLE  and  POLD1  genetic testing should not be restricted to polyposis cases, and the presence of  de novo  mutations, considered.

New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis