Prevalence and Spectrum of Germline and Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome.

About 10-20% of breast/ovarian (BC/OC) cancer patients undergoing germline genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the "Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors" of University Hospital Policlinico "P. Giaccone" of Palermo, were genetically tested for germline variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were -, whereas 67 (7.7%) were carriers of germline VUSs, and 168 (19.2%) harbored germline pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on gene, whereas 38 (64.4%) on . We detected six alterations in and two in with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the -c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.