In:
Journal of Medical Genetics, BMJ, Vol. 56, No. 7 ( 2019-07), p. 453-460
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmedgenet-2018-105834
Sprache:
Englisch
Verlag:
BMJ
Publikationsdatum:
2019
ZDB Id:
2009590-9
SSG:
12
