Novel pleiotropic BRCA2 pathogenic variants in Lebanese families

• Published in: Cancer genetics 2019-02, Vol.231-232, p.32-35
• Main Authors: El-Khoury, Riyad, Hajj, Mirna, Khraibani, Jinan, Audi, Emma, Monsef, Carla, Farra, Chantal
• Format: Article
• Language: English
• Subjects: BRCA2; Breast cancer; Novel pathogenic variants; Ovarian cancer; Pleiotropy
• ISSN: 2210-7762; 2210-7770
• DOI: 10.1016/j.cancergen.2018.12.005

•Novel BRCA2 mutations in two Lebanese families.•Variable expressivity within family members.•Haploinsufficiency and/or mutation-specific dominant negative phenotypes. BRCA1 and BRCA2 associated pathogenic variants are the major cause of familial cases of early onset breast and ovarian cancers. Here we report two novel heterozygous pathogenic variants in exons 18 and 11 of the BRCA2 gene in two Lebanese families. The double nucleotide insertion c.8052_8053dupAA was identified in a 38-year-old Lebanese woman diagnosed with a breast cancer. The patient had a family history of affected first degree relatives. The double nucleotide deletion c.4342_4343delAA was identified in a 67-year-old woman with ovarian cancer. The patient came from a family marked by the occurrence of variable cancers. Her two daughters were also found to carry the deleterious variant. Both genetic aberrations result in a framing error that leads to a premature stop codon giving rise to unstable or truncated proteins. We further discuss two non-mutually exclusive potential scenarios related to the resulting haploinsufficiency and variant-specific dominant negative phenotype that might explain, at least in part, the variable expressivity associated with BRCA2 pathogenic variants.