Uncovering variable neoplasms between ATM protein-truncating and common missense variants using 394 694 UK Biobank exomes

Genes Chromosomes Cancer. 2022 Sep;61(9):523-529. doi: 10.1002/gcc.23042. Epub 2022 Apr 16.


As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10-9 ) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein-coding variants in ATM, three individual missense variants significantly (p < 2 × 10-9 ) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor-related, none overlapped the established ATM PTV-linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.

Keywords: ATM; UK Biobank; missense variants; neoplasms; protein-truncating variants; whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins* / genetics
  • Biological Specimen Banks
  • Breast Neoplasms* / genetics
  • Cell Cycle Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Exome
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Mutation, Missense*
  • Neoplasms* / genetics
  • United Kingdom


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins