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Alternative splicin...
Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants : An ENIGMA report
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- Lopez-Perolio, Irene (author)
- Hospital Clinico San Carlos de Madrid
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- Leman, Raphaël (author)
- Centre François Baclesse
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- Behar, Raquel (author)
- Hospital Clinico San Carlos de Madrid
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show more...
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- Lattimore, Vanessa (author)
- University of Otago
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- Pearson, John F. (author)
- University of Otago
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- Castéra, Laurent (author)
- Centre François Baclesse
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- Martins, Alexandra (author)
- University of Rouen
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- Vaur, Dominique (author)
- Centre François Baclesse
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- Goardon, Nicolas (author)
- Centre François Baclesse
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- Davy, Grégoire (author)
- Centre François Baclesse
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- Garre, Pilar (author)
- Hospital Clinico San Carlos de Madrid
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- García-Barberán, Vanesa (author)
- Hospital Clinico San Carlos de Madrid
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Llovet, Patricia (author)
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- Pérez-Segura, Pedro (author)
- Hospital Clinico San Carlos de Madrid
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- Díaz-Rubio, Eduardo (author)
- Hospital Clinico San Carlos de Madrid
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- Caldés, Trinidad (author)
- Hospital Clinico San Carlos de Madrid
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Hruska, Kathleen S. (author)
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Hsuan, Vickie (author)
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Wu, Sitao (author)
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Pesaran, Tina (author)
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Karam, Rachid (author)
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- Vallon-Christersson, Johan (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Borg, Ake (author)
- Skåne University Hospital
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- Investigators, Kconfab (author)
- University of Melbourne,Peter MacCallum Cancer Centre
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Valenzuela-Palomo, Alberto (author)
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Velasco, Eladio Andrés (author)
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- Southey, Melissa (author)
- University of Melbourne
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- Vreeswijk, Maaike P.G. (author)
- Leiden University Medical Centre
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- Devilee, Peter (author)
- Leiden University Medical Centre
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- Kvist, Anders (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Spurdle, Amanda B. (author)
- QIMR Berghofer Medical Research Institute
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- Walker, Logan C. (author)
- University of Otago
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- Krieger, Sophie (author)
- Centre François Baclesse
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- De La Hoya, Miguel (author)
- Hospital Clinico San Carlos de Madrid
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(creator_code:org_t)
- 2019-03-19
- 2019
- English.
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In: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 56:7, s. 453-460
- Related links:
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http://dx.doi.org/10... (free)
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https://jmg.bmj.com/...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- acmg-amp guidelines
- palb2
- pvs1
- splicing
- variant classification
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Lopez-Perolio, I ...
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Leman, Raphaël
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Behar, Raquel
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Lattimore, Vanes ...
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Pearson, John F.
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Castéra, Laurent
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show more...
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Martins, Alexand ...
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Vaur, Dominique
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Goardon, Nicolas
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Davy, Grégoire
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Garre, Pilar
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García-Barberán, ...
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Llovet, Patricia
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Pérez-Segura, Pe ...
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Díaz-Rubio, Edua ...
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Caldés, Trinidad
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Hruska, Kathleen ...
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Hsuan, Vickie
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Wu, Sitao
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Pesaran, Tina
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Karam, Rachid
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Vallon-Christers ...
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Borg, Ake
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Investigators, K ...
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Valenzuela-Palom ...
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Velasco, Eladio ...
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Southey, Melissa
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Vreeswijk, Maaik ...
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Devilee, Peter
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Kvist, Anders
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Spurdle, Amanda ...
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Walker, Logan C.
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Krieger, Sophie
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De La Hoya, Migu ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Journal of Medic ...
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Lund University