Additional molecular and clinical evidence open the way to definitive IARC classification of the BRCA1 c.5332G > A (p.Asp1778Asn) variant |
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| Institution: | 1. Dipartimento di Diagnostica di Laboratorio, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy;2. UOC Oncologia, Azienda Ospedaliera S. Giovanni - Addolorata, Roma, Italy;3. Dipartimento di Ostetricia e Ginecologia, Divisione di Ginecologia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy;4. Università Cattolica del Sacro Cuore, Roma, Italy;1. Gynecologic Oncology Unit, Women Wealth Area, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy;2. Institute of Neurosurgery Polo Scienze dell''Invecchiamento, Neurologiche ortopediche e della Testa-Collo, Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy |
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| Abstract: | ObjectivesIn silico splicing analysis, a mini-gene assay and splicing data, obtained using RNA from blood samples, have shown that the BRCA1 c.5332G > A variant induces exon 21 skipping. However, despite these evidences, up to date, this variant is unclassified.The aim of this study is to provide further molecular and clinical evidence for the BRCA1 c.5332G > A variant in a patient with high grade serous ovarian carcinoma (HGSOC) to allow a definitive classification of this variant.Design and methodThe effect of the BRCA1 c.5332G > A variant on RNA splicing was evaluated by amplifying regions of BRCA1 from the cDNA of the patient. Loss of heterozygosity (LOH) in tumor tissue was also investigated.ResultsThe c.5332G > A allele causes significantly aberrant splicing of the BRCA1 exon 21. Evaluation of the c.5332A allele in tumor tissue highlights a possible loss of heterozygosity, supporting her pathogenic effect.ConclusionsOur results regarding the c.5332G > A variant confirm that it contributed to predisposition and onset of ovarian carcinoma in the patient. We propose to classify this variant as ‘likely-pathogenic’ (class IV). |
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