Two mutations of BRCA2 gene at exon and splicing site in a woman who underwent oncogenetic counseling

Background Although most BRCA sequence variants are clearly deleterious and unequivocally pathogenetic, several are still classified as variants of unknown significance. Patients and methods We followed families undergoing oncogenetic counseling from risk identification to risk definition by genetic testing and risk management. Results We identified two germline mutations in the BRCA2 gene in a woman with breast and ovarian cancer. One sequence alteration was 859/G>A in exon 7 (V211I). The other second sequence alteration (IVS13-2A>T) affected the splicing site in intron 13. The latter alteration is not yet listed in the Breast Cancer Information Core database. RT–PCR resulted in transcription of a sequence lacking exon 7 and a subsequent anomalous stop codon in exon 9 thereby confirming altered messenger RNA (mRNA) maturation. Amplification of the mutation in intron 13 resulted in transcription of a sequence lacking exon 14 and an anomalous stop codon in exon 15 thereby confirming altered mRNA maturation. Both mutations led to a truncated BRCA2 protein in its carboxy-terminal region. Conclusion The two BRCA2 mutations identified affect mRNA splicing fidelity and play a pathogenetic role in breast and ovarian cancer.