{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T17:33:47Z","timestamp":1793900027649,"version":"4.8.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T00:00:00Z","timestamp":1695081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union's Horizon 2020","award":["634935"],"award-info":[{"award-number":["634935"]}]},{"DOI":"10.13039\/501100004587","name":"ISCIII","doi-asserted-by":"publisher","award":["PI20\/00225"],"award-info":[{"award-number":["PI20\/00225"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Regional Development European Funds","award":["CSI242P18"],"award-info":[{"award-number":["CSI242P18"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["v203477\/Z\/16\/Z"],"award-info":[{"award-number":["v203477\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https:\/\/cordis.europa.eu\/project\/id\/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5\u2032UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A &amp;gt; G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Incorporation of minigene read-outs into an ACMG\/AMP (American College of Medical Genetics and Genomics\/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic\/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/clinchem\/hvad125","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T16:48:13Z","timestamp":1691686093000},"page":"319-338","source":"Crossref","is-referenced-by-count":16,"title":["Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52\n                    <i>CHEK2<\/i>\n                    Splice-Site Variants"],"prefix":"10.1093","volume":"70","author":[{"given":"Lara","family":"Sanoguera-Miralles","sequence":"first","affiliation":[{"name":"Splicing and Genetic Susceptibility to Cancer, Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, Consejo Superior de Investigaciones Cient\u00edficas\u2014Universidad de Valladolid (CSIC-UVa) , Valladolid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Valenzuela-Palomo","sequence":"additional","affiliation":[{"name":"Splicing and Genetic Susceptibility to Cancer, Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, Consejo Superior de Investigaciones Cient\u00edficas\u2014Universidad de Valladolid (CSIC-UVa) , Valladolid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4888-2885","authenticated-orcid":false,"given":"Elena","family":"Bueno-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Splicing and Genetic Susceptibility to Cancer, Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, Consejo Superior de Investigaciones Cient\u00edficas\u2014Universidad de Valladolid (CSIC-UVa) , Valladolid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"Esteban-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory CIBERONC, Hospital Cl\u00ednico San Carlos, IdISSC (Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3681-4319","authenticated-orcid":false,"given":"V\u00edctor","family":"Lorca","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory CIBERONC, Hospital Cl\u00ednico San Carlos, IdISSC (Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Llinares-Burguet","sequence":"additional","affiliation":[{"name":"Splicing and Genetic Susceptibility to Cancer, Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, Consejo Superior de Investigaciones Cient\u00edficas\u2014Universidad de Valladolid (CSIC-UVa) , Valladolid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Garc\u00eda-\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Splicing and Genetic Susceptibility to Cancer, Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, Consejo Superior de Investigaciones Cient\u00edficas\u2014Universidad de Valladolid (CSIC-UVa) , Valladolid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"P\u00e9rez-Segura","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory CIBERONC, Hospital Cl\u00ednico San Carlos, IdISSC (Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-5249","authenticated-orcid":false,"given":"Mar","family":"Infante","sequence":"additional","affiliation":[{"name":"Cancer Genetics, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (CSIC-UVa) , Valladolid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas F","family":"Easton","sequence":"additional","affiliation":[{"name":"Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge , CB1 8RN, Cambridge , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-2009","authenticated-orcid":false,"given":"Peter","family":"Devilee","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Leiden , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike P 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