Genetic testing for germline variants in homologous recombination repair genes, other than BRCA1 and BRCA2, in patients with suspected hereditary cancer syndromes

Arnaut, Daniela; Rodrigues, Pedro; Theisen, Patrícia; Carpinteiro, Dina; Vieira, Luís; Gonçalves, João

http://hdl.handle.net/10400.18/9094

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Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of DNA double-strand breaks. Pathogenic germline variants in BRCA1 and BRCA2 lead to HRR deficiency associated with breast, ovarian, prostate, pancreatic cancers and are sensitive to PARP inhibitors (PARPi). Defects in HRR genes beyond BRCA1/2 could also result in HRR deficiency and sensitize the tumor to PARPi, thus expanding the subset of patients that can benefit from these targeted therapy cancer drugs. We studied 56 DNA samples obtained from patients with personal and family history of cancer. Genes involved in HRR (ATM, BAP1, BLM, BRIP1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D) were analysed by NGS using TruSight® Hereditary Cancer. Sequence alignment and annotation included DRAGEN Enrichment and Variant Interpreter - Illumina®. Variant classification, according to ACMG-AMP 1, was based on VEP, HSF, Alamut, VarSome and several databases (ex. HGMD, gnomAD, dbSNP). Variants of uncertain significance (VUS) were also classified with the stepwise ABC system2. All pathogenic/likely pathogenic SNVs and CNVs were confirmed by Sanger sequencing or MLPA. We identified 156 SNVs and one CNV, of these 125 were benign/likely benign. Seven clinically actionable variants were found in 10.7% of the patients: 3 pathogenic variants in FANCA, FANCD2 and FANCI give rise to premature stop codons and one pathogenic CNV in FANCA (deletion of exons 38 and 39); 2 likely pathogenic variants in BLM and FANCI affecting splicing and one frameshift in FANCG. Classification of 18 VUS with the ABC system resulted in: 8 class 0 (normal finding), 7 class E (potential interest) and 3 class D (low penetrance) variants. In addition, 7 SNVs were classified as hypomorphic alleles. This study confirmed: i) the importance of extending the molecular study beyond BRCA1/2 to other genes involved in HRR, ii) some variants require functional/family studies to establish their pathogenicity, and iii) these genes could potentially be considered for specific and clinical studies involving PARPi therapy.