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. 2019 Jan:63:54-58.
doi: 10.1016/j.clinbiochem.2018.10.004. Epub 2018 Oct 10.

Additional molecular and clinical evidence open the way to definitive IARC classification of the BRCA1 c.5332G > A (p.Asp1778Asn) variant

Angelo Minucci  1 , Maurizio Lalle  2 , Rossella De Leo  3 , Giorgia Mazzuccato  4 , Giovanni Scambia  5 , Andrea Urbani  6 , Anna Fagotti  5 , Paola Concolino  4 , Ettore Capoluongo  6
Affiliations

Additional molecular and clinical evidence open the way to definitive IARC classification of the BRCA1 c.5332G > A (p.Asp1778Asn) variant

Angelo Minucci et al. Clin Biochem. 2019 Jan.

Abstract

Objectives: In 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 method: The 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.

Results: The 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.

Conclusions: Our 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).

Keywords: Exon skipping; Hereditary ovarian cancer; Loss of heterozygosity; Splicing variant.

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