Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition

Abstract

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition.

Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

“…Many studies measure splicing defects by minigene construction or DNA transcript analysis [63,64], while others are developing assays to investigate interactions among enhancers, promoters or transcription factors [65]. The advent of new genome editing technologies allowed functional testing with amplified potentiality.…”

Differentially expressed genes and key molecules of BRCA1/2-mutant breast cancer: evidence from bioinformatics analyses

“…Loss of one copy of functional BRCA1/2 is not clinically apparent, and somatic mutations detection of BRCA genes is affected by cancer cell content and mutation ratio, lacking the accuracy and inherent simplicity, and the accuracy of detection. Although germline and somatic variants of BRCA1/2 have been described, variants in their genetic regions only account for a small proportion of cancer risk, and the majority is currently unknown, which remains a difficulty for genetic testing (Santana Dos Santos et al, 2018). Moreover, BRCA1/2 mutations render tumors more sensitive to drugs that cause DNA cross-linking, such as cisplatin, carboplatin, and mitomycin.…”

HRness in Breast and Ovarian Cancers

“…They present an unknown functional effect on BRCA1 and BRCA2 and cannot currently be classified as either pathogenic or of low clinical significance. A large number of missense variants and virtually all non-coding deep intronic or promoter variants remain of unknown significance (VUS) since they cause subtle changes in protein structure (for missense variants) or in the amount of produced protein (for non-coding variants), being generally difficult to reliably determine their pathogenicity merely from clinical genetic information [133]. A VUS finding should not be considered clinically useful and should not be taken into account for clinical decisions until further evidence emerges to shift interpretation.…”