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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
- Source :
- Human Molecular Genetics, Human Molecular Genetics, 2016, 25 (11), pp.2256-2268. ⟨10.1093/hmg/ddw094⟩, Human Molecular Genetics, Oxford University Press (OUP), 2016, 25 (11), pp.2256-2268. ⟨10.1093/hmg/ddw094⟩, Human Molecular Genetics, 25(11), 2256-2268, Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid, Consejería de Sanidad de la Comunidad de Madrid
- Publication Year :
- 2016
-
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 3.23x10-8. 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 comprised of ?70-80% truncating transcripts, and ?20-30% of in-frame ?9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[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.
- Subjects :
- 0301 basic medicine
Adult
RNA Splicing
[SDV]Life Sciences [q-bio]
DNA Mutational Analysis
Breast Neoplasms
Biology
03 medical and health sciences
Exon
Genetics
Humans
Allele
Molecular Biology
Gene
Genetics (clinical)
ComputingMilieux_MISCELLANEOUS
Aged
Ovarian Neoplasms
Messenger RNA
BRCA1 Protein
Tumor Suppressor Proteins
Alternative splicing
RNA
General Medicine
Articles
Exons
Middle Aged
Splicing regulatory element
3. Good health
Gene Expression Regulation, Neoplastic
Alternative Splicing
030104 developmental biology
RNA splicing
Mutation
Female
RNA Splice Sites
Subjects
Details
- Language :
- English
- ISSN :
- 09646906 and 14602083
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics, Human Molecular Genetics, 2016, 25 (11), pp.2256-2268. ⟨10.1093/hmg/ddw094⟩, Human Molecular Genetics, Oxford University Press (OUP), 2016, 25 (11), pp.2256-2268. ⟨10.1093/hmg/ddw094⟩, Human Molecular Genetics, 25(11), 2256-2268, Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid, Consejería de Sanidad de la Comunidad de Madrid
- Accession number :
- edsair.doi.dedup.....9f80b3e720ea177f5b64e9bec6f99516