ACMG/AMP‐based tentative classification of ATM genetic variants

We classified 56 ATM genetic variants according to a recently proposed ACMG/AMP point system, a Bayesian framework that outperforms the original classification guidelines, and allows for increased flexibility and accuracy in combining different ACMG/AMP criteria and strengths of evidence [25, 26]. In this framework, point‐based variant classification categories are defined as follows: Pathogenic (P) ≥ +10; Likely Pathogenic (LP) + 6 to +9; Variant of Uncertain Significance (VUS) 0 to +5; Likely Benign (LB) –1 to −6; and Benign (B) ≤ −7.

To assign ACMG/AMP scores [27] to individual variants, we based our analysis primarily on recently released (19 January 2022) ATM specifications defined by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (clinicalgenome.org/affiliation/50039/). For some specific variants, we also used ATM specifications elaborated by the Spanish ATM Cancer Susceptibility Variant Interpretation Working Group [28]. Finally, we introduced some ad‐hoc rules, in particular to incorporate mgATM complex readouts (≥2 transcripts) into the classification scheme as PVS1_O/BP7_O codes of variable strength depending on the actual outcome. As a result, we do not intend to provide an ACMG/AMP or ClinGen endorsed final classification of any ATM variant ready to be used in the clinical setting, but rather to highlight the complexity of incorporating complex minigene readouts into an ACMG/AMP‐based classification scheme. A comprehensive description of the classification scheme is provided in Supplementary materials and methods, and supplementary material, Table S3.1–S3.3, and Figure S3A–C. For comparative purposes only, we performed an alternative classification incorporating predictive splicing codes PVS1/PP3/BP4 rather than experimental splicing codes PVS1_O/BP7_O (see supplementary material, Table S3.4).