A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history

Abstract

Heterozygous germ line mutations in the Breast CAncer1 (BRCA1) and BRCA2 genes can lead to a high risk of breast and ovarian cancer, in addition to a significantly increased susceptibility of pancreatic, prostate and male breast cancer. The BRCA2 belongs to the tumor suppressor gene family and the protein encoded by this gene is involved in the repair of chromosomal damage, with an important role in the error-free repair of DNA double strand breaks. After complete sequencing of coding regions and splice junctions of both genes, in a family with breast cancer history, a non previously reported heterozygous mutation in BRCA2 was detected and studied in an Italian healthy female. The direct sequencing disclosed, on exon 15, an insertion (7525_7526insT). The frame shift mutation of BRCA2 causes a disruption of the translational reading frame, resulting in a stop codon 29 amino acids downstream, in the 2538 position of the BRCA2 protein. The mutated allele codifies a truncated protein, lacking the two putative nuclear localization signals (NLSs) that reside within the extreme C-terminal domain of BRCA2. Since this mutant protein not performs a translocation into the nucleus, it is fully non-functional.

A Comprehensive Focus on Global Spectrum ofBRCA1andBRCA2Mutations in Breast Cancer

“…In BRCA2 gene, most of mutations occur in exons 10 and 11 and usually include insertions or deletions which raise the missense alterations and premature stop codon ending in truncated and nonfunctional protein. It was shown that the segments of BRCA2 that were separated out contain double strand break domain (DBD), nuclear localization signal (NLS), and Rad-51 binding motif are located in C-terminal which are critical for BRCA2 function [ 20 ].…”

“…Two new premature stop codon insertion/deletion mutations (7525_7526insT and 6174delT) were detected in exon 15 of BRCA2 in Italian BC women. They occur in C-terminal of protein and are associated with disruption of nuclear localization signals (NLSs) which interfere with BRCA2 nuclear penetration and participation in DNA repair process [ 20 ]. The significance of these alterations is due to their important role in drug resistance especially PARP inhibitors [ 63 ].…”

An overview of breast cancer: Classification and related signaling pathways

“…However, the mutations reported in BRCA2 mainly happen in exons 10 and 11 and always include insertions or deletions; these unwanted changes then cause missense alterations and premature stop codon seen in truncated and completely nonfunctional protein [60] .…”