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.

2.50
Hdl Handle:
http://hdl.handle.net/11287/604102
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.
Authors:
de la Hoya, M.; Soukarieh, O.; López-Perolio, I.; Vega, A.; Walker, L. C.; van Ierland, Y.; Baralle, D.; Santamariña, M.; Lattimore, V.; Wijnen, J. T.; Whiley, P.; Blanco, A.; Raponi, M.; Hauke, J.; Wappenschmidt, B.; Becker, A.; Hansen, T. V. O.; Behar, R.; Niederacher, D.; Arnold, N.; Dworniczak, B.; Steinemann, D.; Faust, U.; Rubinstein, W.; Hulick, P. J.; Houdayer, C.; Caputo, S. M.; Castera, L.; Pesaran, T.; Chao, E.; Brewer, Carole; Southey, M. C.; van Asperen, C. J.; Singer, C. F.; Sullivan, J.; Poplawski, N.; Mai, P.; Peto, J.; Johnson, N.; Burwinkel, B.; Surowy, H.; Bojesen, S.E.; Flyger, H.; Lindblom, A.; Margolin, S.; Chang-Claude, J.; Rudolph, A.; Radice, P.; Galastri, L.; Olson, J. E.; Hallberg, E.; Giles, G. G.; Milne, R. L.; Andrulis, I. L.; Glendon, G.; Hall, P.; Czene, K.; Blows, F.; Shah, M.; Wang, Q.; Dennis, J.; Michailidou, K.; McGuffog, L.; Bolla, M. K.; Antoniou, A. C.; Easton, D. F.; Couch, F. J.; Tavtigian, S.; Vreeswijk, M.; Parsons, M.; Meeks, H.; Martins, A.; Goldgar, D. E.; Spurdle, A. B.
Abstract:
A recent analysis using family history weighting and co-observation classification modeling indicated thatBRCA1c.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 pathogenicBRCA1variant. 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 inciswith 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 aper allele BRCA1expression profile comprised 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 thatBRCA1c.[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 inBRCA1exons 9 or 10, or any otherBRCA1allele 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.
Citation:
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. 2016 Jun 1;25(11):2256-2268
Publisher:
Oxford Journals
Journal:
Human molecular genetics
Issue Date:
23-Mar-2016
URI:
http://hdl.handle.net/11287/604102
DOI:
10.1093/hmg/ddw094
PubMed ID:
27008870
Additional Links:
http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=27008870
Type:
Journal Article
Language:
en
ISSN:
1460-2083
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorde la Hoya, M.en
dc.contributor.authorSoukarieh, O.en
dc.contributor.authorLópez-Perolio, I.en
dc.contributor.authorVega, A.en
dc.contributor.authorWalker, L. C.en
dc.contributor.authorvan Ierland, Y.en
dc.contributor.authorBaralle, D.en
dc.contributor.authorSantamariña, M.en
dc.contributor.authorLattimore, V.en
dc.contributor.authorWijnen, J. T.en
dc.contributor.authorWhiley, P.en
dc.contributor.authorBlanco, A.en
dc.contributor.authorRaponi, M.en
dc.contributor.authorHauke, J.en
dc.contributor.authorWappenschmidt, B.en
dc.contributor.authorBecker, A.en
dc.contributor.authorHansen, T. V. O.en
dc.contributor.authorBehar, R.en
dc.contributor.authorNiederacher, D.en
dc.contributor.authorArnold, N.en
dc.contributor.authorDworniczak, B.en
dc.contributor.authorSteinemann, D.en
dc.contributor.authorFaust, U.en
dc.contributor.authorRubinstein, W.en
dc.contributor.authorHulick, P. J.en
dc.contributor.authorHoudayer, C.en
dc.contributor.authorCaputo, S. M.en
dc.contributor.authorCastera, L.en
dc.contributor.authorPesaran, T.en
dc.contributor.authorChao, E.en
dc.contributor.authorBrewer, Caroleen
dc.contributor.authorSouthey, M. C.en
dc.contributor.authorvan Asperen, C. J.en
dc.contributor.authorSinger, C. F.en
dc.contributor.authorSullivan, J.en
dc.contributor.authorPoplawski, N.en
dc.contributor.authorMai, P.en
dc.contributor.authorPeto, J.en
dc.contributor.authorJohnson, N.en
dc.contributor.authorBurwinkel, B.en
dc.contributor.authorSurowy, H.en
dc.contributor.authorBojesen, S.E.en
dc.contributor.authorFlyger, H.en
dc.contributor.authorLindblom, A.en
dc.contributor.authorMargolin, S.en
dc.contributor.authorChang-Claude, J.en
dc.contributor.authorRudolph, A.en
dc.contributor.authorRadice, P.en
dc.contributor.authorGalastri, L.en
dc.contributor.authorOlson, J. E.en
dc.contributor.authorHallberg, E.en
dc.contributor.authorGiles, G. G.en
dc.contributor.authorMilne, R. L.en
dc.contributor.authorAndrulis, I. L.en
dc.contributor.authorGlendon, G.en
dc.contributor.authorHall, P.en
dc.contributor.authorCzene, K.en
dc.contributor.authorBlows, F.en
dc.contributor.authorShah, M.en
dc.contributor.authorWang, Q.en
dc.contributor.authorDennis, J.en
dc.contributor.authorMichailidou, K.en
dc.contributor.authorMcGuffog, L.en
dc.contributor.authorBolla, M. K.en
dc.contributor.authorAntoniou, A. C.en
dc.contributor.authorEaston, D. F.en
dc.contributor.authorCouch, F. J.en
dc.contributor.authorTavtigian, S.en
dc.contributor.authorVreeswijk, M.en
dc.contributor.authorParsons, M.en
dc.contributor.authorMeeks, H.en
dc.contributor.authorMartins, A.en
dc.contributor.authorGoldgar, D. E.en
dc.contributor.authorSpurdle, A. B.en
dc.date.accessioned2016-03-31T15:48:39Zen
dc.date.available2016-03-31T15:48:39Zen
dc.date.issued2016-03-23en
dc.identifier.citationCombined 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. 2016 Jun 1;25(11):2256-2268en
dc.identifier.issn1460-2083en
dc.identifier.pmid27008870en
dc.identifier.doi10.1093/hmg/ddw094en
dc.identifier.urihttp://hdl.handle.net/11287/604102en
dc.description.abstractA recent analysis using family history weighting and co-observation classification modeling indicated thatBRCA1c.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 pathogenicBRCA1variant. 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 inciswith 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 aper allele BRCA1expression profile comprised 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 thatBRCA1c.[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 inBRCA1exons 9 or 10, or any otherBRCA1allele 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.en
dc.languageENGen
dc.language.isoenen
dc.publisherOxford Journalsen
dc.relation.urlhttp://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=27008870en
dc.rightsArchived with thanks to Human molecular geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleCombined 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.en
dc.typeJournal Articleen
dc.identifier.journalHuman molecular geneticsen
dc.type.versionIn press (epub ahead of print)en

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