Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures

Hum Mutat. 2019 Jan;40(1):36-41. doi: 10.1002/humu.23676. Epub 2018 Nov 20.


We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole-exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal-dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE-deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch-repair function (POLE-exo* /MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations.

Keywords: POLE; PPAP; colorectal cancer; genetic diagnosis; hereditary cancer; mutational signatures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA Polymerase II / genetics*
  • Family
  • Female
  • Germ-Line Mutation / genetics*
  • Humans
  • Male
  • Mutation / genetics*
  • Neoplasms, Multiple Primary / genetics*
  • Neoplasms, Multiple Primary / pathology
  • Pedigree
  • Poly-ADP-Ribose Binding Proteins / genetics*


  • Poly-ADP-Ribose Binding Proteins
  • DNA Polymerase II
  • POLE protein, human