Abstract 242P
Background
The detection and correct interpretation of a mutation as a variant of unknown significance (VUS) is one of the most challenging points in genetic council units (GCU). In the context of hereditary breast and ovarian cancer syndrome (HBOC), approximately 5% to 10% of VUS have been reported in the study of germline mutations of BRCA 1/2 genes. The lack of evidence on the interpretation and management of patients with VUS in BRCA 1/2 increases the difficulty of correct genetic counselling. The aim of this study is to implement the reclassification of VUS obtained in genetic studies of BRCA 1/2 mutation carriers to offer a better understanding and improvement of healthcare quality in GCU.
Methods
A descriptive study of germline mutations in BRCA 1/2 observed in 125 families was conducted in the GCU of the Medical Oncology Department of the University Healthcare Complex of Salamanca between 2001 and 2020. The patients were reclassified through a clinical review using the kConFab, ClinVar and Varsome databases. The reclassification of VUS was performed using the criteria of the International Agency for Research on Cancer (IARC).
Results
A total of 111 VUS were found in BRCA 1/2 genes. Thirty-nine (35.1%) VUS belonged to the BRCA1 mutation, and 72 (64.9%) corresponded to the BRCA2 mutation. In 54 mutations (48.6%), reclassification was possible according to IARC criteria; 28 (25.2%) were reinterpreted as benign mutations, three (2.7%) as pathogenic, 16 (14.4%) as probably benign and seven (6.3%) as probably pathogenic. Seventy-five percent (84/111) of the reclassified VUS were missense. The most frequent associated tumour was breast cancer in 58.6%, followed by ovarian cancer in 16.2%.
Conclusions
According to our results, the analysis and reclassification of VUS allows a better approach to the genetic counselling of patients and their families. Of the total reported VUS, the most common reclassification was to the benign subgroup with a probability of pathogenicity of less than 0.1%. These data suggest that most VUS are polymorphisms. These results allow a better clinical interpretation and contribute to the good management of clinical decisions.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.