Functional assessment of single-nucleotide variations of ATM using prime editing

ATM, a large gene with 63 exons, plays a critical role in the DNA damage response,and its loss-of-function increases cancer risk and affects the prognosis of cancerpatients. However, interpreting the functional impact of ATM variants remainschallenging, because most are variants of uncertain significance (VUSs). Here, weused prime editing and deep learning to assess the functions of all 27,513 possiblesingle nucleotide variants (SNVs) in ATM. By leveraging haploidization and olaparib, aPARP inhibitor, we experimentally evaluated 23,092 SNVs, thereby identifying criticalresidues.