Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Splicing and genetic susceptibility to cancer, Instituto de Biología y Genética Molecular (CSIC-UVa), Valladolid, Spain.
Hum Mutat. 2018 Sep;39(9):1155-1160. doi: 10.1002/humu.23583. Epub 2018 Jul 13.
Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976 + 5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers. We have also detected several isoforms (Δ16-18, Δ17,18, Δ18, and ▼17q ) at different expression levels among carriers and controls. This study remarks the challenge of interpreting genetic variants when multiple alternative isoforms are present, and that caution must be taken when using in silico tools to identify potential spliceogenic variants located in GC-AG introns.
许多 BRCA1 和 BRCA2（BRCA1/2）基因变异已在 mRNA 水平上进行了研究，并因剪接改变而与遗传性乳腺癌和卵巢癌相关。在评估位于共识剪接位点的变异时，计算机工具是可靠的，但对于位于复杂基因组环境中的变异，生物信息学可能不够精确。在这项研究中，我们描述了位于 17 号内含子的 BRCA2 c.7976 + 5G > T 变异，该变异具有非典型的供体位点（GC）。该变异在三个不相关的西班牙家族中被发现，我们已经检测到外显子 17 跳跃是携带者中主要发生的转录本。我们还在携带者和对照组中检测到不同表达水平的几种异构体（Δ16-18、Δ17、18、Δ18 和 ▼17q）。这项研究表明，当存在多种替代异构体时，解释遗传变异具有挑战性，并且在使用计算机工具识别位于 GC-AG 内含子中的潜在剪接变异时必须小心谨慎。
