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. 2020 Dec 3;11(12):1451.
doi: 10.3390/genes11121451.

Five Italian Families with Two Mutations in BRCA Genes

Maria Teresa Vietri  1   2 , Gemma Caliendo  2 , Giovanna D'Elia  2 , Marianna Resse  1   2 , Amelia Casamassimi  1 , Pellegrino Biagio Minucci  1   2 , Concetta Dello Ioio  3 , Michele Cioffi  1   2 , Anna Maria Molinari  1   2
Affiliations

Five Italian Families with Two Mutations in BRCA Genes

Maria Teresa Vietri et al. Genes (Basel). .

Abstract

Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 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 BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, 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 BRCA1 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 BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

Keywords: BRCA1; BRCA2; double heterozygosity (DH); double mutations (DM); hereditary breast and ovarian cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pedigree of family 1 carrying the double heterozygosity (DH) in BRCA1 c.547+2T>A (IVS8+2T>A) and BRCA2 c.2830A>T (p.Lys944Ter). The ages at diagnosis are indicated in brackets.
Figure 2
Figure 2
Pedigree of family 2 carrying the DH in BRCA1 c.3752_3755GTCT (p.Ser1253fs) and BRCA2 c.425+2T>C (IVS4+2T>C). The ages at diagnosis are indicated in brackets.
Figure 3
Figure 3
Pedigree of family 3 carrying the DM in BRCA2 c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T). The ages at diagnosis are indicated in brackets.
Figure 4
Figure 4
Pedigree of family 4 carrying the DM in BRCA2 c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T). The ages at diagnosis are indicated in brackets.
Figure 5
Figure 5
Pedigree of family 5 carrying the DM in BRCA2 c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T). The ages at diagnosis are indicated in brackets.
Figure 6
Figure 6
Cancer types occurring in families with DH and DM. BC: breast cancer; bBC: bilateral breast cancer; OC: ovarian cancer; BOC: breast ovarian cancer; MBC: male breast cancer; PC: prostate cancer; LAC: laryngeal cancer; CC: colon cancer; PAC: pancreatic cancer; LEU: leukemia; BLC: bladder cancer.
See this image and copyright information in PMC

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