Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study

Abstract

Hereditary breast and ovarian cancers are mainly linked to variants in BRCA1/2 genes. Recently, data has shown that identification of BRCA variants has an immediate impact not only in cancer prevention but also in targeted therapeutic approaches. This prospective observational study characterized the overall germline BRCA variant and variant of uncertain significance (VUS) frequency and spectrum in individuals affected by breast (BC) or ovarian cancer (OC) and in healthy individuals at risk by sequencing the entire BRCA genes. Of the 363 probands analyzed, 50 (13.8%) were BRCA1/2 mutated, 28 (7.7%) at BRCA1 and 23 (6.3%) at BRCA2 gene. The variant c.5266dupC p.(Gln1756Profs) was the most frequent alteration, representing 21.4% of the BRCA1 variants and 12.0% of all variants identified. The variant c.6313delA p.(Ile2105Tyrfs) of BRCA2 was the most frequent alteration observed in 6 patients. Interestingly, two new variants were identified in BRCA2. In addition, 25 different VUS were identified; two were reported for the first time in BRCA1 and two in BRCA2. The number of triple-negative BCs was significantly higher in patients with the pathogenic BRCA1/2-variant (36.4%) than in BRCA1/2 VUS (16.0%) and BRCA1/2 wild-type patients (10.7%) (p < 0.001). Our study reveals that the overall frequency of BRCA germline variants in the selected high-risk Italian population is about 13.8%. We believe that our results could have significant implications for preventive strategies for unaffected BRCA-carriers and effective targeted treatments such as PARP inhibitors for patients with BC or OC.

Keywords: BRCA1/2 variant carrier; VUS; breast cancer; genetic testing; risk evaluation.

Figure 1

Pedigree of patient ID 48 with c.6313delA p.(Ile2105Tyrfs) pathogenic variant in the BRCA2 gene. The proband is indicated by a black arrow. Cancer Type and age at cancer diagnosis is indicated in the legend. Symbols: squares = males, circles = females; quadrant shading = cancer affected; slash through square or circle = deceased.

Figure 2

Pedigree of patient ID 886 with c.4928T>C, p.(Val1643Ala) Unclassified variant in BRCA2 gene. The proband is indicated by a black arrow. Cancer Type and age at cancer diagnosis is indicated in the legend. Symbols: squares = males, circles = females; quadrant shading = cancer affected; slash through square or circle = deceased.