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Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for  CHEK2  missense alleles, we developed a yeast-based assay to assess  in vivo  CHEK2-mediated response to DNA damage. Of 25 germline  CHEK2  missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type  CHEK2 . Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case–control studies to have been undertaken. Assay results were largely concordant with consensus predictions of  in silico  tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by  in silico  tools. An  in vivo  assay of cellular response to DNA damage by mutant  CHEK2  alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences.

Response to DNA damage of CHEK2 missense mutations in familial breast cancer