{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T05:52:24Z","timestamp":1794462744739,"version":"4.9.1"},"reference-count":35,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T00:00:00Z","timestamp":1703894400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,12,17]]},"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                     <jats:italic>BRCA1\/2<\/jats:italic> testing is crucial to guide clinical decisions in patients with hereditary breast\/ovarian cancer, but detection of variants of uncertain significance (VUSs) prevents proper management of carriers. The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) <jats:italic>BRCA1\/2<\/jats:italic> Variant Curation Expert Panel (VCEP) has recently developed <jats:italic>BRCA1\/2<\/jats:italic> variant classification guidelines consistent with ClinGen processes, specified against the ACMG\/AMP (American College of Medical Genetics and Genomics\/Association for Molecular-Pathology) classification framework.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The ClinGen-approved <jats:italic>BRCA1\/2-<\/jats:italic>specified ACMG\/AMP classification guidelines were applied to <jats:italic>BRCA1\/2<\/jats:italic> VUSs identified from 2011 to 2022 in a series of patients, retrieving information from the VCEP documentation, public databases, literature and ENIGMA unpublished data. Then, we critically re-evaluated carrier families based on new results and checked consistency of updated classification with main sources for clinical interpretation of <jats:italic>BRCA1\/2<\/jats:italic> variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 166 VUSs detected in 231 index cases, 135 (81.3%) found in 197 index cases were classified by applying <jats:italic>BRCA1\/2-<\/jats:italic>specified ACMG\/AMP criteria: 128 (94.8%) as Benign\/Likely Benign and 7 (5.2%) as Pathogenic\/Likely Pathogenic. The average time from the first report as \u2018VUS\u2019 to classification using this approach was 49.4 months. Considering that 15 of these variants found in 64 families had already been internally reclassified prior to this work, this study provided 121 new reclassifications among the 151 (80.1%) remaining VUSs, relevant to 133\/167 (79.6%) families.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These results demonstrated the effectiveness of new <jats:italic>BRCA1\/2<\/jats:italic> ACMG\/AMP classification guidelines for VUS classification within a clinical cohort, and their important clinical impact. Furthermore, they suggested a cadence of no more than 3 years for regular review of VUSs, which however requires time, expertise and resources.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109694","type":"journal-article","created":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T13:20:27Z","timestamp":1703942427000},"page":"483-489","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Clinical implications of VUS reclassification in a single-centre series from application of ACMG\/AMP classification rules specified for <i>BRCA1\/2<\/i>"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-2412","authenticated-orcid":false,"given":"Giovanni","family":"Innella","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, Bologna, Italy"},{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Ferrari","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Miccoli","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Luppi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, Bologna, Italy"},{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1970-9912","authenticated-orcid":false,"given":"Cristina","family":"Fortuno","sequence":"additional","affiliation":[{"name":"Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3242-8477","authenticated-orcid":false,"given":"Michael T","family":"Parsons","sequence":"additional","affiliation":[{"name":"Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1337-7897","authenticated-orcid":false,"given":"Amanda B","family":"Spurdle","sequence":"additional","affiliation":[{"name":"Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6792-3921","authenticated-orcid":false,"given":"Daniela","family":"Turchetti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, Bologna, Italy"},{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,12,30]]},"reference":[{"key":"2025100520514529000_61.5.483.1","unstructured":"National Institute for Health and Care Excellence (NICE) . Familial Breast Cancer: Classification, Care and Managing Breast Cancer and Related Risks in People with a Family History of Breast Cancer. National Institute for Health and Care Excellence (NICE,"},{"key":"2025100520514529000_61.5.483.2","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2021.0001"},{"key":"2025100520514529000_61.5.483.3","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20880"},{"key":"2025100520514529000_61.5.483.4","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21627"},{"key":"2025100520514529000_61.5.483.5","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318204cfed"},{"key":"2025100520514529000_61.5.483.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pec.2011.04.017"},{"key":"2025100520514529000_61.5.483.7","doi-asserted-by":"crossref","first-page":"viii69","DOI":"10.1093\/annonc\/mdt312","article-title":"Variants of unknown significance in BRCA testing: impact on risk perception, worry, prevention and counseling","volume":"24 Suppl 8","author":"Richter","year":"2013","journal-title":"Ann Oncol"},{"key":"2025100520514529000_61.5.483.8","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-017-5959-3"},{"key":"2025100520514529000_61.5.483.9","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2021.682445","article-title":"Prevalence and spectrum of Germline BRCA1 and BRCA2 variants of uncertain significance in breast\/ovarian cancer: mysterious signals from the genome","volume":"11","author":"Fanale","year":"2021","journal-title":"Front Oncol"},{"key":"2025100520514529000_61.5.483.10","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2022.100459","article-title":"Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, Pancreatic, and prostate cancer: a position paper of Italian scientific societies","volume":"7","author":"Russo","year":"2022","journal-title":"ESMO Open"},{"key":"2025100520514529000_61.5.483.11","doi-asserted-by":"publisher","DOI":"10.1086\/424388"},{"key":"2025100520514529000_61.5.483.12","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025100520514529000_61.5.483.13","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.210"},{"key":"2025100520514529000_61.5.483.14","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2018.00378","article-title":"Dealing with BRCA1\/2 unclassified variants in a cancer Genetics clinic: does Cosegregation analysis help","volume":"9","author":"Zuntini","year":"2018","journal-title":"Front Genet"},{"key":"2025100520514529000_61.5.483.15","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24088"},{"key":"2025100520514529000_61.5.483.16","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/btad179","article-title":"SpliceAI-10k calculator for 445 the prediction of pseudoexonization, intron retention, and exon deletion","volume":"39","author":"Canson","year":"2023","journal-title":"Bioinformatics"},{"key":"2025100520514529000_61.5.483.17","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23818"},{"key":"2025100520514529000_61.5.483.18","unstructured":"Servizio Sanit\u00e0 Pubblica and Regione Emilia-Romagna . \u201cContributo N. 91\/2016: \u201cProtocollo Assistenziale Nelle Donne a Rischio Ereditario Di Tumore Della Mammella E\/O Ovaio\u201d\u201d 2016. Available: http:\/\/salute.regione.emilia- romagna.it\/documentazione\/rapporti\/contributi\/contributi- n- 91- protocollo- assistenziale-nelle-donne-a-rischio-ereditario-di-tumore-della-mammella-e-o-ovaio-2016\/view"},{"key":"2025100520514529000_61.5.483.19","doi-asserted-by":"crossref","DOI":"10.3390\/cancers10120487","article-title":"Role of BRCA mutations in cancer treatment with Poly(ADP-ribose) polymerase (PARP) inhibitors","volume":"10","author":"Faraoni","year":"2018","journal-title":"Cancers (Basel)"},{"key":"2025100520514529000_61.5.483.20","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.207"},{"key":"2025100520514529000_61.5.483.21","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318226fc15"},{"key":"2025100520514529000_61.5.483.22","doi-asserted-by":"publisher","DOI":"10.1007\/s12282-019-00951-w"},{"key":"2025100520514529000_61.5.483.23","doi-asserted-by":"publisher","DOI":"10.1002\/pon.1467"},{"key":"2025100520514529000_61.5.483.24","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12097"},{"key":"2025100520514529000_61.5.483.25","doi-asserted-by":"publisher","DOI":"10.1093\/jlb\/lsx038"},{"key":"2025100520514529000_61.5.483.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0461-z"},{"key":"2025100520514529000_61.5.483.27","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-011-1674-0"},{"key":"2025100520514529000_61.5.483.28","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.212"},{"key":"2025100520514529000_61.5.483.29","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1813800"},{"key":"2025100520514529000_61.5.483.30","unstructured":"Mehta PA , Ebens C . Fanconi anemia. In: Adam MP , ed. GeneReviews\u00ae. Seattle: University of Washington, 2002."},{"key":"2025100520514529000_61.5.483.31","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24449"},{"key":"2025100520514529000_61.5.483.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0478-1"},{"key":"2025100520514529000_61.5.483.33","doi-asserted-by":"publisher","DOI":"10.1136\/jme-2022-108864"},{"key":"2025100520514529000_61.5.483.34","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e31816b5cae"},{"key":"2025100520514529000_61.5.483.35","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15151"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109694","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T03:51:55Z","timestamp":1759722715000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,30]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,4,19]]},"published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1136\/jmg-2023-109694"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109694","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,30]]}}}