Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome

Abstract

About 10–20% of breast/ovarian (BC/OC) cancer patients undergoing germline BRCA1/2 genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline BRCA1/2 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 BRCA 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 BRCA1/2 variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were BRCA-w.t., whereas 67 (7.7%) were carriers of germline BRCA1/2 VUSs, and 168 (19.2%) harbored germline BRCA1/2 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 BRCA1 gene, whereas 38 (64.4%) on BRCA2. We detected six alterations in BRCA1 and two in BRCA2 with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the BRCA1-c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline BRCA1/2 VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.

Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge

“…The genetic analysis for BRCA1/2 was carried out as previously described. 2 , 17 , 18 Sequencing analysis was carried out using Ion 520 Chip (Thermo Fisher Scientific) and Ion Torrent S5 (Thermo Fisher Scientific) instrument. The obtained data were processed with two different software called Amplicon Suite (SmartSeq s.r.l., Novara, Italy) and Ion Reporter Software v.5.14 (Thermo Fisher Scientific).…”

Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength

“…When a LPV/PV was identified in a patient, the genetic test result was considered informative, whereas it was defined not informative, when no PV or LPV was detected, but their presence could not be excluded, or a variant of uncertain significance (VUS) to which it was not possible to attribute a risk value was detected ( 27 ).…”

Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies

“… The use of PARP inhibitors in the neoadjuvant setting remains under evaluation in clinical trials. 13 , 15 In the adjuvant setting, there are no solid prospective data on the use of platinum derivatives in patients with BRCA -related breast cancer. The potential role of PARP inhibitors has been shown in the Olympia trial, where adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer invasive- or distant disease-free survival than placebo.…”

“…The use of PARP inhibitors in the neoadjuvant setting remains under evaluation in clinical trials. 13 , 15 …”