Genetic testing for cancer predisposition leads to the identification of a number of variants with uncertain significance. To some extent, variants of BRCA1/2 have been classified, in contrast to variants of other genes. CHEK2 is a typical example, in which a large number of variants of unknown clinical significance were identified and still remained unclassified. Herein, the CHEK2 variant assessment was performed through an in vivo, yeast-based, functional assay. In total, 120 germline CHEK2 missense variants, distributed along the protein sequence, and two large in-frame deletions were tested, originating from genetic test results in breast cancer families, or selected from the ClinVar database. Of these, 32 missense and two in-frame deletions behaved as non-functional, 73 as functional, and 15 as semi-functional, after comparing growth rates of each strain with positive and negative controls. The majority of non-functional variants were localized in the CHK2 kinase and forkhead-associated domains. In vivo results from the non-functional variants were in agreement with in silico predictions, and, where available, with strong breast cancer family history, to a great extent. The results of the largest, to date, yeast-based assay, evaluating CHEK2 variants, can complement and assist in the classification of rare CHEK2 variants with unclear clinical significance.

Department of Biological Chemistry Medical School National and Kapodistrian University of Athens Athens Greece

Department of Clinical Biochemistry Attikon University General Hospital Medical School National and Kapodistrian University of Athens Athens Greece

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Laboratory of Environmental Mutagenesis and Carcinogenesis Institute of Biosciences and Applications National Centre for Scientific Research Demokritos Athens Greece

Molecular Diagnostics Laboratory INRaSTES National Center for Scientific Research Demokritos Athens Greece

Protein Chemistry Laboratory INRaSTES National Center for Scientific Research Demokritos Athens Greece

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