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https://hdl.handle.net/2440/104174
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dc.contributor.author | de la Hoya, M. | - |
dc.contributor.author | Soukarieh, O. | - |
dc.contributor.author | López-Perolio, I. | - |
dc.contributor.author | Vega, A. | - |
dc.contributor.author | Walker, L.C. | - |
dc.contributor.author | van Ierland, Y. | - |
dc.contributor.author | Baralle, D. | - |
dc.contributor.author | Santamariña, M. | - |
dc.contributor.author | Lattimore, V. | - |
dc.contributor.author | Wijnen, J. | - |
dc.contributor.author | Whiley, P. | - |
dc.contributor.author | Blanco, A. | - |
dc.contributor.author | Raponi, M. | - |
dc.contributor.author | Hauke, J. | - |
dc.contributor.author | Wappenschmidt, B. | - |
dc.contributor.author | Becker, A. | - |
dc.contributor.author | Hansen, T.V.O. | - |
dc.contributor.author | Behar, R. | - |
dc.contributor.author | KConFaB, I. | - |
dc.contributor.author | Niederacher, D. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Human Molecular Genetics, 2016; 25(11):2256-2268 | - |
dc.identifier.issn | 0964-6906 | - |
dc.identifier.issn | 1460-2083 | - |
dc.identifier.uri | http://hdl.handle.net/2440/104174 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Miguel de la Hoya ... Nicola Poplawski ... Niel Johnson ... et al. | - |
dc.language.iso | en | - |
dc.publisher | Oxford University Press | - |
dc.rights | © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com | - |
dc.source.uri | http://dx.doi.org/10.1093/hmg/ddw094 | - |
dc.subject | alleles; alternative splicing; brca1 protein; exons; genes; genes, brca1; rna splicing; rna, messenger genetics; rna | - |
dc.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 | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1093/hmg/ddw094 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1061779 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1010719 | - |
dc.relation.grant | NHMRC | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/209057 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/251553 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/504711 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Poplawski, N. [0000-0002-9372-3325] | - |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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