Five Italian Families with Two Mutations in BRCA Genes

Abstract

Double heterozygosity (DH) in <i>BRCA1</i> and <i>BRCA2</i> genes and double mutation (DM) in <i>BRCA1</i> or <i>BRCA2</i> are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the <i>BRCA1/2</i> genes with a frequency of 0.3% and three probands with DM in the <i>BRCA2</i> gene with a frequency of 0.5%. The DH <i>BRCA1</i> c.547+2T>A (IVS8+2T>A)/<i>BRCA2</i> c.2830A>T (p.Lys944Ter) and <i>BRCA1</i> c.3752_3755GTCT (p.Ser1253fs)/<i>BRCA2</i> c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in <i>BRCA2</i>, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of <i>BRCA1</i> pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that <i>BRCA2</i> pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.