A missense variant effect map for the human tumour suppressor protein CHK2

Abstract

The tumour suppressorCHEK2encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair and inducing apoptosis. CHK2 phosphorylation of the tumour suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell cycle checkpoint role, both germline and somatic variants inCHEK2have been linked to breast and multiple other cancer types. Over 90% of clinical germlineCHEK2missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of aS. cerevisiaelacking its orthologRAD53, we generated a systematic ‘missense variant effect map’ forCHEK2missense variation. Map scores reflect known biochemical features of CHK2 and exhibit good performance in separating pathogenic from benign clinical missense variants. Thus, the missense variant effect map for CHK2 offers value in understanding both known and yet-to-be-observed CHK2 variants.