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

Irene Lopez-Perolio 1 Raphaël Leman 2, 3 Raquel Behar 1 Vanessa Lattimore 4 John F. Pearson 4 Laurent Castéra 2, 3 Alexandra Martins 3 Dominique Vaur 2, 3 Nicolas Goardon 2, 3 Grégoire Davy 2, 3 Pilar Garre 1 Vanesa García-Barberán 1 Patricia Llovet 1 Pedro Pérez-Segura 1 Eduardo Díaz-Rubio 1 Trinidad Caldés 1 Kathleen S. Hruska 5 Vickie Hsuan 6 Sitao Wu 6 Tina Pesaran 6 Rachid Karam 6 Johan Vallon-Christersson 7 Ake Borg 7 Kconfab Investigators 8 Alberto Valenzuela-Palomo 9 Eladio A. Velasco 9 Melissa Southey 8 Maaike P. G. Vreeswijk 10 Peter Devilee 10 Anders Kvist 7 Amanda B Spurdle 11 Logan C. Walker 4 Sophie Krieger 2, 3 Miguel de La Hoya 1
1 IdISSC - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain]
2 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
3 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
4 University of Otago [Dunedin, Nouvelle-Zélande]
5 GeneDx [Gaithersburg, MD, USA]
6 Ambry Genetics [Aliso Viejo, CA, USA]
7 Lund University [Lund]
8 University of Melbourne
9 INGEBI - Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, “Dr. Héctor N. Torres” [Buenos Aires]
10 Leiden University Medical Center (LUMC)
11 QIMR Berghofer Medical Research Institute
Abstract : 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.
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Irene Lopez-Perolio, Raphaël Leman, Raquel Behar, Vanessa Lattimore, John F. Pearson, et al.. Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report. Journal of Medical Genetics, BMJ Publishing Group, 2019, 56 (7), pp.453-460. ⟨10.1136/jmedgenet-2018-105834⟩. ⟨hal-02194498⟩

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