{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T19:18:17Z","timestamp":1768418297968,"version":"3.49.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"11-12","license":[{"start":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T00:00:00Z","timestamp":1758326400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T00:00:00Z","timestamp":1758326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI20\/00225"],"award-info":[{"award-number":["PI20\/00225"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI23\/00047"],"award-info":[{"award-number":["PI23\/00047"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI24\/00267"],"award-info":[{"award-number":["PI24\/00267"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008431","name":"Consejer\u00eda de Educaci\u00f3n, Junta de Castilla y Le\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008431","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Med"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ATM<\/jats:italic>\n                      loss-of-function variants are significantly associated with increased breast cancer risk.\n                      <jats:italic>ATM<\/jats:italic>\n                      exon 7 skipping (\u25b3(E7)) is a naturally-occurring alternative splicing event, which introduces a premature termination codon and represents a form of gene-expression regulation via unproductive splicing. Disruption of splicing regulatory elements (SRE) by variants can lead to mis-splicing, potentially contributing to disease susceptibility. To study the regulatory mechanisms of \u25b3(E7) and the impact of exonic variants on splicing, a combined in silico\/minigene approach was employed, using the construct mgATM_4-9 (exons 4\u20139) that recapitulates this splicing event.\u00a0HEXplorer analysis of\n                      <jats:italic>ATM<\/jats:italic>\n                      exon 7 predicted two splicing enhancer-rich regions (c.665\u2013681 and c.867\u2013898). Deletions of these intervals in mgATM_4-9 significantly increased \u25b3(E7) (57\u201396%), revealing their critical role for exon 7 inclusion. Forty-eight candidate variants (HEXplorer, \u25b3HZEI score\u2009&lt;\u2009-40) within these SRE-rich segments were functionally assayed, 34 of which (71%) impaired exon 7 recognition. Nineteen variants presented strong impacts with high expression of \u25b3(E7)-transcripts (69\u201396%), of which c.668A\u2009&gt;\u2009T, c.680C\u2009&gt;\u2009A and c.680C\u2009&gt;\u2009T exhibited particularly strong effects (4\u201313% full-length transcripts). DeepCLIP analysis suggested that SR proteins SRSF7 and SRSF10 play a positive regulatory role in exon 7 inclusion. Eight variants were classified as likely pathogenic according to ACMG\/AMP-based guidelines. Furthermore, nine missense and two synonymous variants with strong impacts (16\u201329% full-length transcripts) might represent intermediate risk alleles.\u00a0This work collectively demonstrates the intricate nature of\n                      <jats:italic>ATM<\/jats:italic>\n                      exon 7 recognition, regulated by\n                      <jats:italic>cis<\/jats:italic>\n                      -acting SREs, emphasizing the value of in silico predictions for initial variant filtering and minigene assays for dissecting splicing regulation and clinical interpretation of variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Messages<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Frameshift\n                            <jats:italic>ATM<\/jats:italic>\n                            exon 7 skipping is an unproductive alternative splicing event that may represent a form of gene-expression regulation.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Two SRE-rich intervals are involved in exon 7 recognition.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Thirty-four out of 48 tested variants located at these intervals disrupted exon 7 inclusion. Nineteen variants showed strong impacts on splicing.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>All variant types can impair splicing: 23 missense, 7 nonsense, and 4 synonymous variants upregulate exon 7 skipping.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Eight variants were classified as likely pathogenic.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00109-025-02595-0","type":"journal-article","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T10:25:19Z","timestamp":1758363919000},"page":"1447-1460","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unproductive alternative splicing of ATM exon 7: mapping of critical regulatory elements and identification of 34 spliceogenic variants"],"prefix":"10.1007","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-0838","authenticated-orcid":false,"given":"In\u00e9s","family":"Llinares-Burguet","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5548-7114","authenticated-orcid":false,"given":"Lara","family":"Sanoguera-Miralles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Garc\u00eda-\u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ada","family":"Esteban-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1003-2685","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Caloca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8113-1410","authenticated-orcid":false,"given":"Miguel","family":"de la Hoya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4888-2885","authenticated-orcid":false,"given":"Elena","family":"Bueno-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9682-5589","authenticated-orcid":false,"given":"Eladio A.","family":"Velasco-Sampedro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,20]]},"reference":[{"key":"2595_CR1","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1146\/annurev-biochem-060614-034335","volume":"84","author":"TT Paull","year":"2015","unstructured":"Paull TT (2015) Mechanisms of ATM activation. Annu Rev Biochem 84:711\u2013738","journal-title":"Annu Rev Biochem"},{"key":"2595_CR2","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.1016\/j.febslet.2010.05.031","volume":"584","author":"FA Derheimer","year":"2010","unstructured":"Derheimer FA, Kastan MB (2010) Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett 584:3675\u20133681","journal-title":"FEBS Lett"},{"key":"2595_CR3","doi-asserted-by":"publisher","first-page":"699","DOI":"10.21037\/tlcr-23-853","volume":"13","author":"KL Thu","year":"2024","unstructured":"Thu KL, Yoon J-Y (2024) ATM-the gene at the moment in non-small cell lung cancer. Transl Lung Cancer Res 13:699\u2013705","journal-title":"Transl Lung Cancer Res"},{"key":"2595_CR4","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1126\/science.7792600","volume":"268","author":"K Savitsky","year":"1995","unstructured":"Savitsky K, Bar-Shira A, Gilad S et al (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749\u20131753","journal-title":"Science"},{"key":"2595_CR5","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1007\/s10689-021-00248-y","volume":"21","author":"F Lesueur","year":"2022","unstructured":"Lesueur F, Easton DF, Renault A-L et al (2022) First international workshop of the ATM and cancer risk group (4\u20135 december 2019). Fam Cancer 21:211\u2013227","journal-title":"Fam Cancer"},{"key":"2595_CR6","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1001\/jamaoncol.2021.3701","volume":"7","author":"FC Hsu","year":"2021","unstructured":"Hsu FC, Roberts NJ, Childs E et al (2021) Risk of pancreatic cancer among individuals with pathogenic variants in the ATM gene. JAMA Oncol 7:1664\u20131668","journal-title":"JAMA Oncol"},{"key":"2595_CR7","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1056\/NEJMe2035083","volume":"384","author":"SA Narod","year":"2021","unstructured":"Narod SA (2021) Which genes for hereditary breast cancer? N Engl J Med 384:471\u2013473","journal-title":"N Engl J Med"},{"key":"2595_CR8","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1056\/NEJMoa1913948","volume":"384","author":"L Dorling","year":"2021","unstructured":"Dorling L, Carvalho S, Allen J et al (2021) Breast cancer risk genes \u2014 association analysis in more than 113,000 women. N Engl J Med 384:428\u2013439","journal-title":"N Engl J Med"},{"key":"2595_CR9","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1056\/NEJMoa2005936","volume":"384","author":"C Hu","year":"2021","unstructured":"Hu C, Hart SN, Gnanaolivu R et al (2021) A population-based study of genes previously implicated in breast cancer. N Engl J Med 384:440\u2013451","journal-title":"N Engl J Med"},{"key":"2595_CR10","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41571-021-00491-3","volume":"18","author":"WD Foulkes","year":"2021","unstructured":"Foulkes WD (2021) The ten genes for breast (and ovarian) cancer susceptibility. Nat Rev Clin Oncol 18:259\u2013260","journal-title":"Nat Rev Clin Oncol"},{"key":"2595_CR11","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1093\/jnci\/djaa167","volume":"113","author":"S Yadav","year":"2020","unstructured":"Yadav S, LaDuca H, Polley EC et al (2020) Racial and ethnic differences in multigene hereditary cancer panel test results for women with breast cancer. JNCI J Natl Cancer Inst 113:1429\u20131433","journal-title":"JNCI J Natl Cancer Inst"},{"key":"2595_CR12","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1001\/jamaoncol.2021.6204","volume":"8","author":"KP Lowry","year":"2022","unstructured":"Lowry KP, Geuzinge HA, Stout NK et al (2022) Breast cancer screening strategies for women with ATM, CHEK2, and PALB2 pathogenic variants: a comparative modeling analysis. JAMA Oncol 8:587\u2013596","journal-title":"JAMA Oncol"},{"key":"2595_CR13","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s41580-022-00545-z","volume":"24","author":"LE Marasco","year":"2023","unstructured":"Marasco LE, Kornblihtt AR (2023) The physiology of alternative splicing. Nat Rev Mol Cell Biol 24:242\u2013254","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2595_CR14","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/nrm.2016.139","volume":"18","author":"KS Manning","year":"2017","unstructured":"Manning KS, Cooper TA (2017) The roles of RNA processing in translating genotype to phenotype. Nat Rev Mol Cell Biol 18:102\u2013114","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2595_CR15","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41576-022-00556-8","volume":"24","author":"ME Rogalska","year":"2023","unstructured":"Rogalska ME, Vivori C, Valc\u00e1rcel J (2023) Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects. Nat Rev Genet 24:251\u2013269","journal-title":"Nat Rev Genet"},{"key":"2595_CR16","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nrg775","volume":"3","author":"L Cartegni","year":"2002","unstructured":"Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285\u2013298","journal-title":"Nat Rev Genet"},{"key":"2595_CR17","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1016\/j.febslet.2005.02.047","volume":"579","author":"N Lopez-Bigas","year":"2005","unstructured":"Lopez-Bigas N, Audit B, Ouzounis C et al (2005) Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett 579:1900\u20131903","journal-title":"FEBS Lett"},{"key":"2595_CR18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007231","volume":"14","author":"CL Rhine","year":"2018","unstructured":"Rhine CL, Cygan KJ, Soemedi R et al (2018) Hereditary cancer genes are highly susceptible to splicing mutations. PLoS Genet 14:e1007231","journal-title":"PLoS Genet"},{"key":"2595_CR19","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1158\/1078-0432.CCR-09-2564","volume":"16","author":"DJ Sanz","year":"2010","unstructured":"Sanz DJ, Acedo A, Infante M et al (2010) A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast\/ovarian cancer patients. Clin Cancer Res 16:1957\u20131967","journal-title":"Clin Cancer Res"},{"key":"2595_CR20","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1038\/embor.2009.170","volume":"10","author":"D Baralle","year":"2009","unstructured":"Baralle D, Lucassen A, Buratti E (2009) Missed threads. The impact of pre-mRNA splicing defects on clinical practice. EMBO Rep 10:810\u2013816","journal-title":"EMBO Rep"},{"key":"2595_CR21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.2144\/000112208","volume":"41","author":"G Singh","year":"2006","unstructured":"Singh G, Cooper TA (2006) Minigene reporter for identification and analysis of cis elements and trans factors affecting pre-mRNA splicing. Biotechniques 41:177\u2013181","journal-title":"Biotechniques"},{"key":"2595_CR22","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1002\/humu.22725","volume":"36","author":"A Acedo","year":"2015","unstructured":"Acedo A, Hern\u00e1ndez-Moro C, Curiel-Garc\u00eda \u00c1 et al (2015) Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. Hum Mutat 36:210\u2013221","journal-title":"Hum Mutat"},{"key":"2595_CR23","doi-asserted-by":"publisher","first-page":"3562","DOI":"10.3390\/cancers16213562","volume":"16","author":"I Llinares-Burguet","year":"2024","unstructured":"Llinares-Burguet I, Sanoguera-Miralles L, Valenzuela-Palomo A et al (2024) Splicing dysregulation of non-canonical GC-5\u2032 splice sites of breast cancer susceptibility genes ATM and PALB2. Cancers 16:3562","journal-title":"Cancers"},{"key":"2595_CR24","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.3390\/cancers13112845","volume":"13","author":"E Bueno-Mart\u00ednez","year":"2021","unstructured":"Bueno-Mart\u00ednez E, Sanoguera-Miralles L, Valenzuela-Palomo A et al (2021) RAD51D aberrant splicing in breast cancer: identification of splicing regulatory elements and minigene-based evaluation of 53 DNA variants. Cancers 13:2845","journal-title":"Cancers"},{"key":"2595_CR25","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1002\/path.6243","volume":"262","author":"L Sanoguera-Miralles","year":"2024","unstructured":"Sanoguera-Miralles L, Llinares-Burguet I, Bueno-Mart\u00ednez E et al (2024) Comprehensive splicing analysis of the alternatively spliced CHEK2 exons 8 and 10 reveals three enhancer\/silencer-rich regions and 38 spliceogenic variants. J Pathol 262:395\u2013409","journal-title":"J Pathol"},{"key":"2595_CR26","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1038\/s41588-022-01293-8","volume":"55","author":"R Dawes","year":"2023","unstructured":"Dawes R, Bournazos AM, Bryen SJ et al (2023) Splicevault predicts the precise nature of variant-associated mis-splicing. Nat Genet 55:324\u2013332","journal-title":"Nat Genet"},{"key":"2595_CR27","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1038\/s41588-024-01872-x","volume":"56","author":"B Fair","year":"2024","unstructured":"Fair B, Najar CFBA, Zhao J et al (2024) Global impact of unproductive splicing on human gene expression. Nat Genet 56:1851\u20131861","journal-title":"Nat Genet"},{"key":"2595_CR28","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1002\/path.5979","volume":"258","author":"E Bueno-Mart\u00ednez","year":"2022","unstructured":"Bueno-Mart\u00ednez E, Sanoguera-Miralles L, Valenzuela-Palomo A et al (2022) Minigene-based splicing analysis and ACMG\/AMP-based tentative classification of 56 ATM variants. J Pathol 258:83\u2013101","journal-title":"J Pathol"},{"key":"2595_CR29","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3389\/fgene.2019.00503","volume":"10","author":"E Fraile-Bethencourt","year":"2019","unstructured":"Fraile-Bethencourt E, Valenzuela-Palomo A, D\u00edez-G\u00f3mez B et al (2019) Minigene splicing assays identify 12 spliceogenic variants of BRCA2 exons 14 and 15. Front Genet 10:503","journal-title":"Front Genet"},{"key":"2595_CR30","doi-asserted-by":"publisher","first-page":"10681","DOI":"10.1093\/nar\/gku736","volume":"42","author":"S Erkelenz","year":"2014","unstructured":"Erkelenz S, Theiss S, Otte M et al (2014) Genomic HEXploring allows landscaping of novel potential splicing regulatory elements. Nucleic Acids Res 42:10681\u201310697","journal-title":"Nucleic Acids Res"},{"key":"2595_CR31","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1002\/humu.24074","volume":"41","author":"D Canson","year":"2020","unstructured":"Canson D, Glubb D, Spurdle AB (2020) Variant effect on splicing regulatory elements, branchpoint usage, and pseudoexonization: strategies to enhance bioinformatic prediction using hereditary cancer genes as exemplars. Hum Mutat 41:1705\u20131721","journal-title":"Hum Mutat"},{"key":"2595_CR32","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1002\/humu.24091","volume":"41","author":"H Tubeuf","year":"2020","unstructured":"Tubeuf H, Charbonnier C, Soukarieh O et al (2020) Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements. Hum Mutat 41:1811\u20131829","journal-title":"Hum Mutat"},{"key":"2595_CR33","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41525-025-00498-0","volume":"10","author":"DM Canson","year":"2025","unstructured":"Canson DM, Llinares-Burguet I, Fortuno C et al (2025) TP53 minigene analysis of 161 sequence changes provides evidence for role of spatial constraint and regulatory elements on variant-induced splicing impact. NPJ Genomic Med 10:37","journal-title":"NPJ Genomic Med"},{"key":"2595_CR34","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan K, Panagiotopoulou SK, McRae JF et al (2019) Predicting splicing from primary sequence with deep learning. Cell 176:535-548.e24","journal-title":"Cell"},{"key":"2595_CR35","first-page":"7099","volume":"48","author":"AGB Gr\u00f8nning","year":"2020","unstructured":"Gr\u00f8nning AGB, Doktor TK, Larsen SJ et al (2020) DeepCLIP: predicting the effect of mutations on protein-RNA binding with deep learning. Nucleic Acids Res 48:7099\u20137118","journal-title":"Nucleic Acids Res"},{"key":"2595_CR36","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1002\/humu.22456","volume":"35","author":"GR de Garibay","year":"2014","unstructured":"de Garibay GR, Acedo A, Garc\u00eda-Casado Z et al (2014) Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants. Hum Mutat 35:53\u201357","journal-title":"Hum Mutat"},{"key":"2595_CR37","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/s12885-015-1259-0","volume":"15","author":"M Gabriel","year":"2015","unstructured":"Gabriel M, Delforge Y, Deward A et al (2015) Role of the splicing factor SRSF4 in cisplatin-induced modifications of pre-mRNA splicing and apoptosis. BMC Cancer 15:227","journal-title":"BMC Cancer"},{"key":"2595_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.100929","volume":"23","author":"Y Kadota","year":"2020","unstructured":"Kadota Y, Jam FA, Yukiue H et al (2020) Srsf7 establishes the juvenile transcriptome through age-dependent alternative splicing in mice. iScience 23:100929","journal-title":"iScience"},{"key":"2595_CR39","doi-asserted-by":"publisher","first-page":"7077","DOI":"10.1093\/nar\/gkr306","volume":"39","author":"J Kralovicova","year":"2011","unstructured":"Kralovicova J, Hwang G, Asplund aC et al (2011) Compensatory signals associated with the activation of human GC 5\u2019 splice sites. Nucleic Acids Res 39:7077\u20137091","journal-title":"Nucleic Acids Res"},{"key":"2595_CR40","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1261\/rna.037044.112","volume":"19","author":"S Erkelenz","year":"2013","unstructured":"Erkelenz S, Mueller WF, Evans MS et al (2013) Position-dependent splicing activation and repression by SR and hnRNP proteins rely on common mechanisms. RNA 19:96\u2013102","journal-title":"RNA"},{"key":"2595_CR41","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1261\/rna.078879.121","volume":"27","author":"L Shkreta","year":"2021","unstructured":"Shkreta L, Delannoy A, Salvetti A, Chabot B (2021) SRSF10: an atypical splicing regulator with critical roles in stress response, organ development, and viral replication. RNA 27:1302\u20131317","journal-title":"RNA"},{"key":"2595_CR42","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/nature02288","volume":"427","author":"C Shin","year":"2004","unstructured":"Shin C, Feng Y, Manley JL (2004) Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427:553\u2013558","journal-title":"Nature"},{"key":"2595_CR43","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1016\/j.celrep.2016.10.071","volume":"17","author":"L Shkreta","year":"2016","unstructured":"Shkreta L, Toutant J, Durand M et al (2016) Srsf10 connects DNA damage to the alternative splicing of transcripts encoding apoptosis, cell-cycle control, and DNA repair factors. Cell Rep 17:1990\u20132003","journal-title":"Cell Rep"},{"key":"2595_CR44","doi-asserted-by":"publisher","first-page":"R141","DOI":"10.1186\/gb-2008-9-9-r141","volume":"9","author":"A Corvelo","year":"2008","unstructured":"Corvelo A, Eyras E (2008) Exon creation and establishment in human genes. Genome Biol 9:R141","journal-title":"Genome Biol"},{"key":"2595_CR45","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1074\/jbc.R700035200","volume":"283","author":"KJ Hertel","year":"2008","unstructured":"Hertel KJ (2008) Combinatorial control of exon recognition. J Biol Chem 283:1211\u20131215","journal-title":"J Biol Chem"},{"key":"2595_CR46","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1016\/j.ajhg.2024.08.002","volume":"111","author":"PJ Sullivan","year":"2024","unstructured":"Sullivan PJ, Quinn JMW, Wu W et al (2024) SpliceVarDB: a comprehensive database of experimentally validated human splicing variants. Am J Hum Genet 111:2164\u20132175","journal-title":"Am J Hum Genet"},{"key":"2595_CR47","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/BF00210743","volume":"90","author":"M Krawczak","year":"1992","unstructured":"Krawczak M, Reiss J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41\u201354","journal-title":"Hum Genet"},{"key":"2595_CR48","doi-asserted-by":"publisher","first-page":"3494","DOI":"10.1093\/nar\/gkl498","volume":"34","author":"E Buratti","year":"2006","unstructured":"Buratti E, Baralle M, Baralle FE (2006) Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res 34:3494\u20133510","journal-title":"Nucleic Acids Res"},{"key":"2595_CR49","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1038\/nature05676","volume":"446","author":"LF Lareau","year":"2007","unstructured":"Lareau LF, Inada M, Green RE et al (2007) Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446:926\u2013929","journal-title":"Nature"},{"key":"2595_CR50","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","volume":"66","author":"AN Blackford","year":"2017","unstructured":"Blackford AN, Jackson SP (2017) ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell 66:801\u2013817","journal-title":"Mol Cell"},{"key":"2595_CR51","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1002\/1098-1004(200009)16:3<232::AID-HUMU6>3.0.CO;2-L","volume":"16","author":"K Laake","year":"2000","unstructured":"Laake K, Jansen L, Hahnemann JM et al (2000) Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum Mutat 16:232\u2013246","journal-title":"Hum Mutat"},{"key":"2595_CR52","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1086\/302418","volume":"64","author":"SN Teraoka","year":"1999","unstructured":"Teraoka SN, Telatar M, Becker-Catania S et al (1999) Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet 64:1617\u20131631","journal-title":"Am J Hum Genet"},{"key":"2595_CR53","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/ajmg.a.20601","volume":"126 A","author":"T D\u00f6rk","year":"2004","unstructured":"D\u00f6rk T, Bendix-Waltes R, Wegner RD, Stumm M (2004) Slow progression of Ataxia-telangiectasia with double missense and in frame splice mutations. Am J Med Genet 126 A:272\u2013277","journal-title":"Am J Med Genet"},{"key":"2595_CR54","first-page":"1505","volume":"19","author":"J Soukupova","year":"2008","unstructured":"Soukupova J, Dundr P, Kliebl Z, Pohlreich P (2008) Contribution of mutations in ATM to breast cancer development in the Czech population. Oncol Rep 19:1505\u20131510","journal-title":"Oncol Rep"},{"key":"2595_CR55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006691","volume":"13","author":"E Fraile-Bethencourt","year":"2017","unstructured":"Fraile-Bethencourt E, D\u00edez-G\u00f3mez B, Vel\u00e1squez-Zapata V et al (2017) Functional classification of DNA variants by hybrid minigenes: identification of 30 spliceogenic variants of BRCA2 exons 17 and 18. PLoS Genet 13:e1006691","journal-title":"PLoS Genet"},{"key":"2595_CR56","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3389\/fgene.2018.00188","volume":"9","author":"E Fraile-Bethencourt","year":"2018","unstructured":"Fraile-Bethencourt E, Valenzuela-Palomo A, D\u00edez-G\u00f3mez B et al (2018) Identification of eight spliceogenic variants in BRCA2 exon 16 by minigene assays. Front Genet 9:188","journal-title":"Front Genet"},{"key":"2595_CR57","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1002\/path.5268","volume":"248","author":"E Fraile-Bethencourt","year":"2019","unstructured":"Fraile-Bethencourt E, Valenzuela-Palomo A, D\u00edez-G\u00f3mez B et al (2019) Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays. J Pathol 248:409\u2013420","journal-title":"J Pathol"},{"key":"2595_CR58","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.3390\/cancers12123771","volume":"12","author":"L Sanoguera-Miralles","year":"2020","unstructured":"Sanoguera-Miralles L, Valenzuela-Palomo A, Bueno-Mart\u00ednez E et al (2020) Comprehensive functional characterization and clinical interpretation of 20 splice-site variants of the RAD51C gene. Cancers 12:3771","journal-title":"Cancers"},{"key":"2595_CR59","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1002\/path.5839","volume":"256","author":"A Valenzuela-Palomo","year":"2022","unstructured":"Valenzuela-Palomo A, Bueno-Mart\u00ednez E, Sanoguera-Miralles L et al (2022) Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants. J Pathol 256:321\u2013334","journal-title":"J Pathol"},{"key":"2595_CR60","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1093\/clinchem\/hvad125","volume":"70","author":"L Sanoguera-Miralles","year":"2024","unstructured":"Sanoguera-Miralles L, Valenzuela-Palomo A, Bueno-Mart\u00ednez E et al (2024) Systematic minigene-based splicing analysis and tentative clinical classification of 52 CHEK2 splice-site variants. Clin Chem 70:319\u2013338","journal-title":"Clin Chem"},{"key":"2595_CR61","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1089\/1066527041410418","volume":"11","author":"G Yeo","year":"2004","unstructured":"Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377\u2013394","journal-title":"J Comput Biol"},{"key":"2595_CR62","doi-asserted-by":"publisher","first-page":"3568","DOI":"10.1093\/nar\/gkg616","volume":"31","author":"L Cartegni","year":"2003","unstructured":"Cartegni L, Wang J, Zhu Z et al (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568\u20133571","journal-title":"Nucleic Acids Res"},{"key":"2595_CR63","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1093\/bioinformatics\/btp124","volume":"25","author":"F Piva","year":"2009","unstructured":"Piva F, Giulietti M, Nocchi L, Principato G (2009) Spliceaid: a database of experimental RNA target motifs bound by splicing proteins in humans. Bioinformatics 25:1211\u20131213","journal-title":"Bioinformatics"},{"key":"2595_CR64","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405\u2013424","journal-title":"Genet Med"},{"key":"2595_CR65","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1093\/clinchem\/hvaa250","volume":"67","author":"L Feliubadal\u00f3","year":"2021","unstructured":"Feliubadal\u00f3 L, Moles-Fern\u00e1ndez A, Santamari\u00f1a-Pena M et al (2021) A collaborative effort to define classification criteria for ATM variants in hereditary cancer patients. Clin Chem 67:518\u2013533","journal-title":"Clin Chem"},{"key":"2595_CR66","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1016\/j.ajhg.2024.08.022","volume":"111","author":"ME Richardson","year":"2024","unstructured":"Richardson ME, Holdren M, Brannan T et al (2024) Specifications of the ACMG\/AMP variant curation guidelines for the analysis of germline ATM sequence variants. Am J Hum Genet 111:2411\u20132426","journal-title":"Am J Hum Genet"}],"container-title":["Journal of Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-025-02595-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00109-025-02595-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-025-02595-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T04:38:03Z","timestamp":1765514283000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00109-025-02595-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,20]]},"references-count":66,"journal-issue":{"issue":"11-12","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["2595"],"URL":"https:\/\/doi.org\/10.1007\/s00109-025-02595-0","relation":{},"ISSN":["0946-2716","1432-1440"],"issn-type":[{"value":"0946-2716","type":"print"},{"value":"1432-1440","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,20]]},"assertion":[{"value":"24 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval for this study was obtained from the Ethics Committee of the Spanish National Research Council-CSIC (28\/05\/2018).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}