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Åke Borg

Åke Borg

Principal investigator

Åke Borg

Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants : An ENIGMA report


  • Irene Lopez-Perolio
  • Raphaël Leman
  • Raquel Behar
  • Vanessa Lattimore
  • John F. Pearson
  • Laurent Castéra
  • Alexandra Martins
  • Dominique Vaur
  • Nicolas Goardon
  • Grégoire Davy
  • Pilar Garre
  • Vanesa García-Barberán
  • Patricia Llovet
  • Pedro Pérez-Segura
  • Eduardo Díaz-Rubio
  • Trinidad Caldés
  • Kathleen S. Hruska
  • Vickie Hsuan
  • Sitao Wu
  • Tina Pesaran
  • Rachid Karam
  • Johan Vallon-Christersson
  • Ake Borg
  • Kconfab Investigators
  • Alberto Valenzuela-Palomo
  • Eladio Andrés Velasco
  • Melissa Southey
  • Maaike P.G. Vreeswijk
  • Peter Devilee
  • Anders Kvist
  • Amanda B. Spurdle
  • Logan C. Walker
  • Sophie Krieger
  • Miguel De La Hoya

Summary, in English

Background: PALB2 monoallelic loss-of-function germ-line variants confer a breast cancer risk comparable to the average BRCA2 pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-function variants in PALB2 - without incurring overprediction - is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. Methods: Alternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2 c.212-1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant. Results: We identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies. Conclusions: PVS1 is not necessarily warranted for splice site variants targeting four PALB2 acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenic without further evidences. Our study puts a warning in up to five PALB2 genetic variants that are currently reported as pathogenic/likely pathogenic in ClinVar.


  • Breastcancer-genetics
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year







Journal of Medical Genetics





Document type

Journal article


BMJ Publishing Group


  • Cancer and Oncology


  • acmg-amp guidelines
  • palb2
  • pvs1
  • splicing
  • variant classification




  • ISSN: 0022-2593