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Type: Journal article
Title: Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms
Author: de la Hoya, M.
Soukarieh, O.
López-Perolio, I.
Vega, A.
Walker, L.
van Ierland, Y.
Baralle, D.
Santamariña, M.
Lattimore, V.
Wijnen, J.
Whiley, P.
Blanco, A.
Raponi, M.
Hauke, J.
Wappenschmidt, B.
Becker, A.
Hansen, T.
Behar, R.
KConFaB, I.
Niederacher, D.
et al.
Citation: Human Molecular Genetics, 2016; 25(11):2256-2268
Publisher: Oxford University Press
Issue Date: 2016
ISSN: 0964-6906
Statement of
Miguel de la Hoya ... Nicola Poplawski ... Niel Johnson ... et al.
Abstract: A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10⁻⁸ . Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70–80% truncating transcripts, and ≈20–30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function. We confirm that BRCA1 c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20–30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
Keywords: alleles; alternative splicing; brca1 protein; exons; genes; genes, brca1; rna splicing; rna, messenger genetics; rna
Rights: © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:
RMID: 0030046085
DOI: 10.1093/hmg/ddw094
Grant ID:
Appears in Collections:Medicine publications

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