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We aimed at identifying and classifying spliceogenic <jats:italic>ATM<\/jats:italic> variants detected in subjects of the large\u2010scale sequencing project BRIDGES. A total of 381 variants at the intron\u2013exon boundaries were identified, 128 of which were predicted to be spliceogenic. After further filtering, we ended up selecting 56 variants for splicing analysis. Four functional minigenes (mgATM) spanning exons 4\u20139, 11\u201317, 25\u201329, and 49\u201352 were constructed in the splicing plasmid pSAD. Selected variants were genetically engineered into the four constructs and assayed in MCF\u20107\/HeLa cells. Forty\u2010eight variants (85.7%) impaired splicing, 32 of which did not show any trace of the full\u2010length (FL) transcript. A total of 43 transcripts were identified where the most prevalent event was exon\/multi\u2010exon skipping. Twenty\u2010seven transcripts were predicted to truncate the ATM protein. A tentative ACMG\/AMP (American College of Medical Genetics and Genomics\/Association for Molecular Pathology)\u2010based classification scheme that integrates mgATM data allowed us to classify 29 <jats:italic>ATM<\/jats:italic> variants as pathogenic\/likely pathogenic and seven variants as likely benign. Interestingly, the likely pathogenic variant c.1898+2T&gt;G generated 13% of the minigene FL\u2010transcript due to the use of a noncanonical GG\u20105\u2019\u2010splice\u2010site (0.014% of human donor sites). Circumstantial evidence in three <jats:italic>ATM<\/jats:italic> variants (leakiness uncovered by our mgATM analysis together with clinical data) provides some support for a dosage\u2010sensitive expression model in which variants producing \u226530% of FL\u2010transcripts would be predicted benign, while variants producing \u226413% of FL\u2010transcripts might be pathogenic. \u00a9 2022 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5979","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T04:00:00Z","timestamp":1655524800000},"page":"83-101","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Minigene\u2010based splicing analysis and <scp>ACMG<\/scp>\/<scp>AMP<\/scp>\u2010based tentative classification of 56 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