https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=39062721&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 390627212024072720240730
2073-44251572024Jul18GenesGenes (Basel)In Silico Prediction of BRCA1 and BRCA2 Variants with Conflicting Clinical Interpretation in a Cohort of Breast Cancer Patients.94310.3390/genes15070943Germline 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' and unaffected carriers' 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.StellaStefaniaSDepartment of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy.VitaleSilvia RitaSR0000-0002-7948-3580Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy.MassiminoMicheleM0000-0001-5896-8573Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy.Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy.MartoranaFedericaF0000-0001-5062-2914Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.TornabeneIreneIDepartment of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.Division of Pathology, Humanitas Istituto Clinico Catanese, 95045 Catania, Italy.TomarchioCristinaC0000-0002-1044-1008Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy.DragoMelissaMDepartment of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy.PavoneGiulianaGDepartment of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.Medical Oncology Unit, Humanitas Istituto Clinico Catanese, 95045 Catania, Italy.GorgoneCristinaCIstituto Oncologico del Mediterraneo-IOM, 95029 Catania, Italy.BaroneChiaraCMedical Genetics, ASP, 96100 Siracusa, Italy.BiancaSebastianoSMedical Genetics, ARNAS Garibaldi, 95123 Catania, Italy.ManzellaLiviaLDepartment of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy.engJournal Article20240718
SwitzerlandGenes (Basel)1015510972073-44250BRCA2 Protein0BRCA1 Protein0BRCA2 protein, human0BRCA1 protein, humanIMHumansFemaleBreast NeoplasmsgeneticsBRCA2 ProteingeneticsBRCA1 ProteingeneticsComputer SimulationMiddle AgedAdultGenetic Predisposition to DiseaseGenetic TestingmethodsGerm-Line MutationAgedCohort StudiesBRCA1BRCA2NGSPROVEANPolyPhen-2SIFTVUSbreast cancerconflicting interpretation of pathogenicity (CIP)genetic testin silico toolsmutation tasterThe authors declare no conflicts of interest.202462820247102024711202472814512024727104420247271102024718epublish39062721PMC1127643710.3390/genes15070943genes15070943Sullivan T., Thirthagiri E., Chong C.E., Stauffer S., Reid S., Southon E., Hassan T., Ravichandran A., Wijaya E., Lim J., et al. Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer. Hum. 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