The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Åke Borg

Åke Borg

Principal investigator

Åke Borg

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

Author

  • 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
Show all

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.

Department/s

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

Publishing year

2019

Language

English

Pages

453-460

Publication/Series

Journal of Medical Genetics

Volume

56

Issue

7

Document type

Journal article

Publisher

BMJ Publishing Group

Topic

  • Cancer and Oncology

Keywords

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

Status

Published

ISBN/ISSN/Other

  • ISSN: 0022-2593