RT Journal Article
SR Electronic
T1 Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 453
OP 460
DO 10.1136/jmedgenet-2018-105834
VO 56
IS 7
A1 Lopez-Perolio, Irene
A1 Leman, Raphaël
A1 Behar, Raquel
A1 Lattimore, Vanessa
A1 Pearson, John F
A1 Castéra, Laurent
A1 Martins, Alexandra
A1 Vaur, Dominique
A1 Goardon, Nicolas
A1 Davy, Grégoire
A1 Garre, Pilar
A1 García-Barberán, Vanesa
A1 Llovet, Patricia
A1 Pérez-Segura, Pedro
A1 Díaz-Rubio, Eduardo
A1 Caldés, Trinidad
A1 Hruska, Kathleen S
A1 Hsuan, Vickie
A1 Wu, Sitao
A1 Pesaran, Tina
A1 Karam, Rachid
A1 Vallon-Christersson, Johan
A1 Borg, Ake
A1 Investigators, kConFab
A1 Valenzuela-Palomo, Alberto
A1 Velasco, Eladio A
A1 Southey, Melissa
A1 Vreeswijk, Maaike P G
A1 Devilee, Peter
A1 Kvist, Anders
A1 Spurdle, Amanda B
A1 Walker, Logan C
A1 Krieger, Sophie
A1 de la Hoya, Miguel
YR 2019
UL http://jmg.bmj.com/content/56/7/453.abstract
AB 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.