Page 29 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
BRCA VUS in breast cancer in MENA region

Table 1. (Continued)
Region Country Authors Year of Numbers Number of Methods Covered gene region
publication of patients VUS detected (s)
North Africa Morocco Taazite 2012 40 50 Direct sequencing BRCA1 and BRCA2
et al.
15
North Africa Tunisia Ben Ayed-Guerfali 2021 134 11 NGS BRCA1 and BRCA2
et al. 29
North Africa Tunisia Fourati 2014 66 9 Direct sequencing BRCA1: exons 5, 20, and
et al. 27 part of exon 11 - BRCA2:
exons 10 and part of
exon 11
North Africa Tunisia Hamdi 2021 354 1 NGS BRCA1 and BRCA2
et al. 30
North Africa Tunisia Mahfoudh 2012 24 15 Direct sequencing BRCA1
et al. 25
North Africa Tunisia Msolly and Kassab 28 2015 17 31 Direct sequencing BRCA1 and BRCA2
North Africa Tunisia Riahi 2015 48 38 Direct sequencing BRCA1 and BRCA2
et al. 26
North Africa Tunisia Troudi 2008 32 6 Direct sequencing BRCA1
et al. 24
North Africa Tunisia Troudi 2007 36 10 Direct sequencing BRCA1 and BRCA2
et al. 23
Abbreviations: BRCA: Breast cancer gene; HDA: Helicase-dependent amplification; HRM: High-resolution melting; MLPA: Multiplex
ligation-dependent probe amplification; NGS: Next-generation sequencing; VUS: Variants of unknown significance.

mutational hotspots that account for a combined 54.3% variants are less common, with most introns showing
of all reported variants. Specifically, exon 10 harbors 44 1 – 3 variants. In addition, there are two variants in an
variants, representing 29.1% of the total, while exon 11 unspecified exon and three in an unspecified intron. This
contains 38 variants, constituting 25.2% of all reported distribution pattern, characterized by a high concentration
variants. The next most affected regions exhibit a marked in exon 11 (37.2%) and a more dispersed pattern across
decrease in variant frequency: exon 16 with seven variants other regions, highlights the complex mutational landscape
(4.6%), exon 19 with six variants (4%), exon 15 with five of BRCA2 in the MENA population.
variants (3.3%), and exons 2 and 7, each with four variants,
both representing a total of 5.4%. The remaining exons 3.4. VUS in BRCA1 and BRCA2
and introns show a further decrease in variant frequency, In our extensive analysis, after filtering and eliminating
with many locations harboring only 1 – 3 variants each, duplicate variants, we identified a total of 385 distinct
collectively accounting for the remaining 28.4% of VUS within the BRCA genes: 151 variants were located
variants. Notably, intronic variants are less common, with in BRCA1, and 234 were found in BRCA2. These variants
most introns containing only 1 – 2 variants each. The 3’ included 276 missense variants, with 110 in BRCA1 and
untranslated region (UTR) region also shows a single 166 in BRCA2, as well as four non-sense variants, equally
variant. distributed with two in each gene. Furthermore, we
An analysis of 234 BRCA2 VUS in the MENA region identified 31 synonymous variants, consisting of 14 in
reveals a non-uniform distribution across the gene, with BRCA1 and 17 in BRCA2. We also detected eight in-frame
significant clustering in specific exons. Exon 11 emerges deletions (IFD), evenly split between the two genes, and
as the primary mutational hotspot, harboring 87 variants 52 intronic variants, with 15 in BRCA1 and 37 in BRCA2.
(37.2% of the total), underscoring its potential critical role In addition, we identified that individual cases such as
in BRCA2 functionality and BC susceptibility. Exon 10 one in-frame insertion-deletion (IFID) and one in-frame
follows with 21 variants (9%), while exons 19 and 27 each substitution, both in BRCA2, were noted, along with a
contain 11 variants (4.7%). Exons 3, 14, and intron 2 show single variant in the 5’UTR and one splice donor site, both
seven variants (3% each), and exons 9 and 15 each harbor in BRCA2. Notably, ten variants had no explicitly defined
six variants (2.6% each). The remaining exons exhibit mutation type, with six in BRCA1 and four in BRCA2.
fewer variants, typically ranging from 1 – 5 each. Intronic Figure 3 provides a visual representation illustrating the

Volume 9 Issue 1 (2025) 21 doi: 10.36922/ejmo.5800