{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:28:32Z","timestamp":1788272912843,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s NextGenerationEU","award":["CUP E63C22002080006"],"award-info":[{"award-number":["CUP E63C22002080006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Germline BRCA1\/2 alteration has been linked to an increased risk of hereditary breast and ovarian cancer syndromes. As a result, genetic testing, based on NGS, allows us to identify a high number of variants of uncertain significance (VUS) or conflicting interpretation of pathogenicity (CIP) variants. The identification of CIP\/VUS is often considered inconclusive and clinically not actionable for the patients\u2019 and unaffected carriers\u2019 management. In this context, their assessment and classification remain a significant challenge. The aim of the study was to investigate whether the in silico prediction tools (PolyPhen-2, SIFT, Mutation Taster and PROVEAN) could predict the potential clinical impact and significance of BRCA1\/2 CIP\/VUS alterations, eventually impacting the clinical management of Breast Cancer subjects. In a cohort of 860 BC patients, 10.6% harbored BRCA1 or BRCA2 CIP\/VUS alterations, mostly observed in BRCA2 sequences (85%). Among them, forty-two out of fifty-five alterations were predicted as damaging, with at least one in silico that used tools. Prediction agreement of the four tools was achieved in 45.5% of patients. Moreover, the highest consensus was obtained in twelve out of forty-two (28.6%) mutations by considering three out of four in silico algorithms. The use of prediction tools may help to identify variants with a potentially damaging effect. The lack of substantial agreement between the different algorithms suggests that the bioinformatic approaches should be combined with the personal and family history of the cancer patients.<\/jats:p>","DOI":"10.3390\/genes15070943","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T16:51:12Z","timestamp":1721321472000},"page":"943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["In Silico Prediction of BRCA1 and BRCA2 Variants with Conflicting Clinical Interpretation in a Cohort of Breast Cancer Patients"],"prefix":"10.3390","volume":"15","author":[{"given":"Stefania","family":"Stella","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7948-3580","authenticated-orcid":false,"given":"Silvia Rita","family":"Vitale","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5896-8573","authenticated-orcid":false,"given":"Michele","family":"Massimino","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014San Marco\u201d, 95123 Catania, Italy"},{"name":"Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5062-2914","authenticated-orcid":false,"given":"Federica","family":"Martorana","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Tornabene","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Division of Pathology, Humanitas Istituto Clinico Catanese, 95045 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1044-1008","authenticated-orcid":false,"given":"Cristina","family":"Tomarchio","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Drago","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Pavone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Medical Oncology Unit, Humanitas Istituto Clinico Catanese, 95045 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Gorgone","sequence":"additional","affiliation":[{"name":"Istituto Oncologico del Mediterraneo\u2014IOM, 95029 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Barone","sequence":"additional","affiliation":[{"name":"Medical Genetics, ASP, 96100 Siracusa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Bianca","sequence":"additional","affiliation":[{"name":"Medical Genetics, ARNAS Garibaldi, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Manzella","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/humu.24154","article-title":"Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer","volume":"42","author":"Sullivan","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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