Characterizing Portuguese Families Identified and Followed in a Tertiary Portuguese Hospital with the c.9382C>T (p.Arg3128Ter) Pathogenic Variant in the BRCA2 gene: Origins, Prevalence and Clinical Implications

Abstract

Introduction: Breast (BC) and ovarian cancers (OC) pose significant health challenges for women worldwide due to their high prevalence and associated morbidity and mortality. Genetic factors, particularly Pathogenic /Likely Pathogenic variants in the BRCA1 and BRCA2 genes, play a crucial role in the development of these diseases. In Portugal, the c.156_157insAlu insertion is the most frequent BRCA2 variant amid carriers. Amongst the population of the Oncogenetic Consultation/ Unidade Local de Saúde de São João - Centro Hospitalar Universitário São João (ULSSJ-CHUSJ)), the c.9382C>T (p.Arg3128Ter) variant ranks second. This study focuses on families carrying the c.9382C>T variant aiming to determine the origins of this variant in the Portuguese population; assess its incidence, penetrance, and risk; and attempt to understand the clinical implications for carriers. Materials & Methods: This is a retrospective observational cohort study that investigates patients and relatives carrying the BRCA2 c.9382C>T (p.Arg3128Ter) variant, attending the Oncogenetic Consultation at ULSSJ-CHUSJ since 2006. Carriers and tested relatives with negative results were included, while those with unavailable data were excluded. Data were collected from physical and digital clinical records. The innovative "genotype-restricted likelihood" (GRL) method was applied. Methodology for the result presentation involved descriptive statistics and narrative. Results: Of the total of 239 BRCA families of ULSSJ-CHUSJ, 154 carry BRCA2 variants. This study comprised 13 families carrying the BRCA2 c.9382C>T (p.Arg3128Ter) variant with a total of 386 individuals (176M:210F) of which 99 underwent the genetic test, with 53 revealing to be carriers (20M:33F) and 46 non-carriers (19M:27F). Regarding carriers, 43,64% developed cancer: 15 had BC (14F:1M) - three of these had bilateral BC - two had gastric cancer (2M) and one had OC (1F). The mean age at the first diagnosis was 42 years (for female BC) and 56 years (for OC). The founding effect of the variant could not be ascertained due to the geographic dispersion of individuals after detailed research of ancestrally. Applying the GRL method we obtained a relative risk for female BC of 15.8-fold at the age of 20 years, 1.4-fold at the age of 40 years, and a similar risk to the general population at the age of 60 years or above. For OC we achieved a relative risk of 0.5-fold at the age of 20 years, 1.4-fold at the age of 40 years, and a similar risk to the general population at the age of 60 years or above. The female BC incidence has a maximum at the age interval of 60 to 64 years of age with the OC incidence with a maximum at the age interval of 70 to 74 years of age. Regarding the disease penetrance in families, it was not possible to calculate due to the small number of carriers in the study and the lack of information about genotype/phenotype in many individuals. Conclusion: To our knowledge, this is the first study to attempt to stratify the risk of BC and OC associated with this variant. Such would allow to establish and apply a much more personalized surveillance program to these carriers. The overrated risk obtained by GRL regarding BC, specifically at the age of 20 years - mainly related to the low-studied population - might be reduced through a national-based multicentric study.