Autor(es): Theisen, Patrícia ; Rodrigues, Pedro ; Silva, Catarina ; Carpinteiro, Dina ; Ribeiro, L. ; Carreiro, Helena ; Gervásio, H. ; Leal da Silva, José ; Vieira, Luís ; Gonçalves, João
Data: 2020
Identificador Persistente: http://hdl.handle.net/10400.18/7445
Origem: Repositório Científico do Instituto Nacional de Saúde
Assunto(s): Cancer; Hereditary Cancer; BRCA1; BRCA2; ATM; Double Heterozigosity; Breast Cancer; Ovarian Cancer; Cancro Hereditário; Doenças Genéticas
Introduction: Hereditary breast and ovarian cancer (HBOC) is estimated to represent 5-10% of all breast and ovarian cancer cases. Pathogenic germline variants in BRCA1 and BRCA2 account for 25% of familial cases. The identification of genetic defects in HBOC patients allows detection of carriers that can benefit from cancer risk management protocols, and predictive genetic testing to at-risk family members, after appropriate genetic counseling. Two female patients with a personal and family history of cancer were studied by next-generation sequencing (NGS). Methods: NGS using TruSight Cancer Panel (Illumina) followed by bioinformatic analysis of 18 genes associated with HBOC was performed. Pathogenic variants were confirmed by Sanger sequencing. Results: A rare event of double heterozigosity for pathogenic variants was identified in both patients: patient A was heterozygous for BRCA1:c.2037delinsCC, p.(Lys679Asn*4) and ATM:c.3802delG, p.(Val1268*) and patient B carried both BRCA2:c.6001dupT, p.(Ser2001Phefs*2) and ATM:3435_3436delTGinsA, p.(Asp1145Glufs*11). After genetic counseling, three relatives of patient A were analyzed: while one of her two healthy sons was heterozygous for the ATM variant, the other was a double heterozygote for BRCA1:c.2037delinsCC and ATM:c.3802delG; a female cousin, recently diagnosed with breast cancer, was a carrier of ATM:c.3802delG only. Conclusions: The identification of these two rare cases of double heterozigosity for pathogenic variants in BRCA1/BRCA2 and ATM genes, highlights the importance of using NGS-gene panel testing in HBOC. If molecular analysis had been restricted to BRCA genes only, the pathogenic ATM variants would have been missed in both families, depriving them of appropriate genetic counseling and cancer risk management.
