Objectives: Hereditary breast and ovarian cancer (HBOC) follows an autosomal dominant inheritance pattern of cancer susceptibility genes. The risk of developing this disease is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. The advent of massive genetic sequencing technologies has expanded the mutational spectrum of this hereditary syndrome, thereby increasing the number of variants of uncertain clinical significance (VUS) detected by genetic testing.
Methods: A prevalence study of HBOC was performed within 2,928 families from the Region of Murcia, in southeastern Spain. Genetic testing enabled the identification of recurrent pathogenic variants and founder mutations, which were mainly related to the BRCA1 and BRCA2 genes. VUS testing was performed using a prioritization algorithm designed by our working group.
Results: Variants c.68_69del, c.212+1G>A, and c.5123C>A were detected in 30 % of BRCA1 carriers, whereas exon 2 deletion concurrent with c.3264dupT, c.3455T>G and c.9117G>A variants were found in 30 % of BRCA2 carriers. A total of 16 VUS (15 %) were prioritized.
Conclusions: The genotype-phenotype correlation observed in our study is consistent with the scientific literature. Furthermore, the founder effect of c.1918C>T (BRCA1) and c.8251_8254del (ATM) was verified in the Murcian population, whereas exon 2 deletion (BRCA2) was proven to be a Spanish founder mutation. Our algorithm enabled us to prioritize potentially pathogenic VUS that required further testing to determine their clinical significance and potential role in HBOC.
Keywords: founder effect; hereditary breast and ovarian cancer; mutational spectrum; prioritization; recurrent pathogenic variants; variants of uncertain clinical significance.
© 2023 the author(s), published by De Gruyter, Berlin/Boston.