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Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report
- Source :
- Journal of Medical Genetics (JMG); 2019, Vol. 56 Issue: 7 p453-460, 8p
- Publication Year :
- 2019
-
Abstract
- BackgroundPALB2monoallelic loss-of-functiongerm-line variants confer a breast cancer risk comparable to the average BRCA2pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-functionvariants 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.MethodsAlternative 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 PALB2c.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.ResultsWe 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.ConclusionsPVS1 is not necessarily warranted for splice site variants targeting four PALB2acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenicwithout further evidences. Our study puts a warning in up to five PALB2genetic variants that are currently reported as pathogenic/likely pathogenicin ClinVar.
Details
- Language :
- English
- ISSN :
- 00222593 and 14686244
- Volume :
- 56
- Issue :
- 7
- Database :
- Supplemental Index
- Journal :
- Journal of Medical Genetics (JMG)
- Publication Type :
- Periodical
- Accession number :
- ejs50409212
- Full Text :
- https://doi.org/10.1136/jmedgenet-2018-105834