Page 49 - EJMO-9-1

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

et al., which reported that missense variants constituted The fact that 14.5% of the variants were not reported
60
a significant proportion of VUS in BRCA1 and BRCA2. in ClinVar, and 2.1% were reported without an attributed
Interestingly, our analysis revealed a higher number of VUS classification, highlights gaps in current databases. These
in BRCA2 compared to BRCA1, a result consistent with gaps suggest the need for further research and a more
the findings of other researchers. This disparity may be comprehensive approach to include all relevant variants in
53
attributed to the larger size of the BRCA2 gene or potentially public databases. Literature supports this view, indicating
different mutational mechanisms affecting the two genes. that a significant portion of identified BRCA variants
remain unclassified or absent from major public databases,
In addition, our study detected 31 synonymous VUS,
with a nearly equal distribution between BRCA1 and suggesting an under-reporting issue.
BRCA2. This finding is significant, as recent research has Notably, 16.1% of variants remain classified as VUS.
demonstrated that synonymous can influence gene function While this is a substantial proportion, it underscores
through alterations in splicing or mRNA stability, challenging ongoing challenges in variant classification. Previous
the traditional view of their neutrality. The presence of 52 studies have reported that a significant percentage of BRCA
61
intronic variants, predominantly in BRCA2, underscores the variants remain as VUS due to limitations in existing
importance of investigating non-coding regions in genetic classification methodologies. For instance, a 2021 study
testing. This aligns with the growing body of evidence found that up to 80% of BRCA1 and BRCA2 variants had
suggesting that intronic variants can significantly affect uncertain clinical significance. It is important to note that
60
gene function by altering splicing mechanisms. Moreover, the MENA region is underrepresented in genomic studies,
59
the identification of rare variant types, such as IFD, IFID, with less than 0.01% of the samples in the Genome-Wide
and variants in UTRs, emphasizes the diverse mutational Association Studies Catalog and less than 0.8% of the
spectrum present in BRCA1 and BRCA2. samples in the Genome Aggregation Database originating
64
from MENA populations. This underrepresentation
4.4. Reclassification of VUS in BRCA can complicate the interpretation of genetic variants,
The reclassification results of BRCA VUS provide valuable potentially resulting in a higher proportion being classified
insights and underscore several trends observed in recent as VUS.
literature on this topic. Finally, the fact that only 2.1% of the variants were
The reclassification of 30.4% of BRCA VUS as benign conclusively reclassified as pathogenic or likely pathogenic
or likely benign represents a positive development and is consistent with other findings in the field. Achieving
aligns with existing literature. For instance, one study more precise classifications requires robust and extensive
reported a downgrading rate of 69.42% for BRCA1 and genetic and functional evidence.
72.41% for BRCA2 variants. Similarly, Macklin et al.
62
63
showed that 75% of the variants initially classified as VUS 5. Conclusion and perspectives
were reclassified as likely benign. These trends suggest Our study emphasizes the critical need for more
that many VUS is being downgraded to benign statuses as comprehensive and systematic analyses to gain a deeper
more data becomes available, which is crucial for patient understanding of the genetic landscape of BC within the
management and reducing unnecessary anxiety over these MENA region. The ongoing reclassification of VUS is
genetic findings. 63 paramount for elucidating their clinical relevance, which
However, the persistence of conflicting interpretations will, in turn, enhance the effectiveness of genetic counseling
of pathogenicity in 34.8% of cases highlights significant for patients affected by BC. Our findings reveal significant
challenges. Conflicting interpretations are not unique to gaps and challenges in variant classification, underscoring
our dataset; it has been reported that a considerable fraction the urgent need for increased research efforts specifically
of BRCA variants have conflicting interpretations. For targeting the MENA region, a demographic that remains
example, Eccles et al. demonstrated that the identification notably underrepresented in genomic studies.
62
and management of genetic variants with conflicting To advance this field, it is imperative to establish
interpretations of pathogenicity is one of the key challenges standardized classification protocols that promote more
in clinical genetic testing. This complexity stems from accurate interpretations of genetic variants. Such measures
differences in variant evaluation criteria and the dynamic would not only improve the reliability of genetic testing
nature of genetic evidence, which evolves continuously outcomes but also facilitate personalized medicine
over time. The inconsistency in interpretations emphasizes approaches in BC management. Ultimately, collaborative
the need for standardized, universally accepted guidelines efforts among geneticists, clinicians, and healthcare
to harmonize variant classification. providers are essential to address the unique genetic factors

Volume 9 Issue 1 (2025) 41 doi: 10.36922/ejmo.5800