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

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