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.
Highlights
Since the discovery of BRCA1 and BRCA2 genes, genetic testing requests have been steadily increasing
As regards the meaning of variants, the Italian Association of Medical Oncology (AIOM) adopts the classification criteria proposed by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, according to the International Agency for Research on Cancer (IARC) recommendations [11], considering a classification system of variants into five classes: Benign, Likely Benign, Variant of Uncertain Significance (VUS, class III), Likely Pathogenic, and Pathogenic [12]
Based on a Breast and Ovarian Cancer BRCA System database harvested at the University Hospital Policlinico “P. Giaccone” of Palermo, the aim of this retrospective investigation was to describe the typology and gene location of germline variants of unknown significance detected in BRCA1 and BRCA2 coding sequences and splicing sites of BC or OC patients in order to investigate the prevalence and spectrum of these inherited genetic variants observed in Southern Italy
Summary
Since the discovery of BRCA1 and BRCA2 genes, genetic testing requests have been steadily increasing. Giaccone” of Palermo, the aim of this retrospective investigation was to describe the typology and gene location of germline variants of unknown significance detected in BRCA1 and BRCA2 coding sequences and splicing sites of BC or OC patients in order to investigate the prevalence and spectrum of these inherited genetic variants observed in Southern Italy. Identified BRCA variants have been classified according to the criteria developed by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium (https://enigmaconsortium.org/) and IARC recommendations [11], using a system of classification in five classes: benign (class I), likely benign (class II), variant of uncertain significance (VUS, class III), likely pathogenic (class IV), and pathogenic (class V). The identified BRCA1/2 VUS was named according to the systematic nomenclature of the recommendations for the description of sequence variants established by the Human Genome Variation Society (HGVS) with authorization by the HGVS, Human Variome Project (HVP), and the Human Genome Organization (HUGO) [29]
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