{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:51:33Z","timestamp":1791244293715,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Instituto de Salud Carlos III","award":["PI20_00110"],"award-info":[{"award-number":["PI20_00110"]}]},{"name":"Spanish Instituto de Salud Carlos III","award":["PI24_00267"],"award-info":[{"award-number":["PI24_00267"]}]},{"name":"the Spanish Ministry of Economy and Innovation"},{"name":"European Regional Development FEDER Funds","award":["PI25\/00744"],"award-info":[{"award-number":["PI25\/00744"]}]},{"name":"European Regional Development FEDER Funds","award":["DTS24\/00083"],"award-info":[{"award-number":["DTS24\/00083"]}]},{"name":"European Regional Development FEDER Funds","award":["PI22\/00589"],"award-info":[{"award-number":["PI22\/00589"]}]},{"name":"European Regional Development FEDER Funds","award":["PI19\/01424"],"award-info":[{"award-number":["PI19\/01424"]}]},{"name":"European Regional Development FEDER Funds","award":["INT24\/00023"],"award-info":[{"award-number":["INT24\/00023"]}]},{"name":"European Regional Development FEDER Funds","award":["INT20\/00071"],"award-info":[{"award-number":["INT20\/00071"]}]},{"name":"Autonomous Government of Galicia","award":["IN607B2025\/09"],"award-info":[{"award-number":["IN607B2025\/09"]}]},{"DOI":"10.13039\/100008061","name":"Mutua Madrile\u00f1a Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Germline loss-of-function variants in BRCA1 and BRCA2 are established drivers of hereditary breast and ovarian cancer, often acting through aberrant splicing. However, not all spliceogenic changes are pathogenic, and many variants remain classified as uncertain due to insufficient experimental evidence and challenges in applying the ACMG\/AMP variant interpretation framework to splicing alterations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we examined the splicing outcomes of 17 variants\u201410 in BRCA1 [c.135-2A&amp;gt;G; c.135-5T&amp;gt;C; c.5074+1G&amp;gt;C; c.5332+2_5332+4del; c.5333-8C&amp;gt;T; c.5335C&amp;gt;G p.(Gln1779Glu); c.302-24_302-22del; c.302-23A&amp;gt;G; c.547+57T&amp;gt;C; c.4096+34C&amp;gt;G] and 7 in BRCA2 [c.-39-5delT; c.67+3A&amp;gt;G; c.425G&amp;gt;A p.(Ser142Asn); c.425G&amp;gt;T p.(Ser142Ile); c.517-13_517-9del; c.681+5G&amp;gt;C; c.67+84_67+85del]\u2014identified in families with suspected hereditary breast and\/or ovarian cancer. Depending on sample availability, we assessed splicing either on carrier-derived mRNA or via splicing-reporter minigene assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eight variants triggered aberrant splicing, while 9 showed no spliceogenic effect. Our findings, combined in some cases with previously published data, allowed us to apply the PVS1_(RNA) criterion at full strength to some variants. For others, residual full-length transcripts or in-frame mis-spliced isoforms precluded full application of PVS1_(RNA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Following ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel specifications based on ACMG\/AMP guidelines, we classified 4 variants as pathogenic or likely pathogenic, 10 as benign or likely benign, and 3 as uncertain significance. This comprehensive analysis of splicing defects refines the clinical classification of BRCA1 and BRCA2 variants and highlights the value of combining experimental and computational evidence to enhance genetic risk assessment in hereditary cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/clinchem\/hvaf177","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T13:03:44Z","timestamp":1764162224000},"page":"266-280","source":"Crossref","is-referenced-by-count":2,"title":["Splicing Predictions, Splicing Assays, and Variant Classification Using ACMG\/AMP Guidelines: Challenges Observed with\n                    <i>BRCA1<\/i>\n                    and\n                    <i>BRCA2<\/i>\n                    Variants"],"prefix":"10.1093","volume":"72","author":[{"given":"Marta","family":"Santamari\u00f1a","sequence":"first","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9089-6765","authenticated-orcid":false,"given":"Olivia","family":"Fuentes-R\u00edos","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Blanco-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"Rodr\u00edguez-Lage","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Crujeiras-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"S\u00e1nchez de Abajo","sequence":"additional","affiliation":[{"name":"Servicio de An\u00e1lisis Cl\u00ednicos y Bioqu\u00edmica Cl\u00ednica, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria , Las Palmas de Gran Canar\u00eda ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Galego-Carro","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Coedo-Costa","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-6726","authenticated-orcid":false,"given":"Miguel E","family":"Aguado-Barrera","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Sampayo","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Servicio de Ginecolog\u00eda, Hospital Cl\u00ednico Universitario de Santiago de Compostela (SERGAS) , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Carracedo","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III , Madrid ,","place":["Spain"]},{"name":"Grupo de Medicina Xen\u00f3mica-CIMUS-Universidade de Santiago de Compostela , Santiago de Compostela ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"de la Hoya","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Hospital Cl\u00ednico San Carlos, IdISSC (Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos) , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7416-5137","authenticated-orcid":false,"given":"Ana","family":"Vega","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Servicio Galego de Sa\u00fade (SERGAS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"2026020307471856200_hvaf177-B1","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1001\/jama.2017.7112","article-title":"Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers","volume":"317","author":"Kuchenbaecker","year":"2017","journal-title":"JAMA"},{"key":"2026020307471856200_hvaf177-B2","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1200\/JCO.21.02112","article-title":"Cancer risks associated with BRCA1 and BRCA2 pathogenic variants","volume":"40","author":"Li","year":"2022","journal-title":"J 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