Genetic, functional, and histopathological evaluation of two C‐terminal BRCA1 missense variants
Identifieur interne : 000F23 ( Pmc/Corpus ); précédent : 000F22; suivant : 000F24Genetic, functional, and histopathological evaluation of two C‐terminal BRCA1 missense variants
Auteurs : P K Lovelock ; S. Healey ; W. Au ; E Y M. Sum ; A. Tesoriero ; E M Wong ; S. Hinson ; R. Brinkworth ; A. Bekessy ; O. Diez ; L. Izatt ; E. Solomon ; M. Jenkins ; H. Renard ; J. Hopper ; P. Waring ; Kconfab Investigators ; S V Tavtigian ; D. Goldgar ; G J Lindeman ; J E Visvader ; F J Couch ; B R Henderson ; M. Southey ; G. Chenevix-Trench ; A B Spurdle ; M A BrownSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2005.
Abstract
The vast majority of
To elucidate the effect of two
Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype
A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of
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DOI: 10.1136/jmg.2005.033258
PubMed: 15923272
PubMed Central: 2564506
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PMC:2564506Le document en format XML
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Hinson</name></author><author><name sortKey="Brinkworth, R" sort="Brinkworth, R" uniqKey="Brinkworth R" first="R" last="Brinkworth">R. Brinkworth</name></author><author><name sortKey="Bekessy, A" sort="Bekessy, A" uniqKey="Bekessy A" first="A" last="Bekessy">A. Bekessy</name></author><author><name sortKey="Diez, O" sort="Diez, O" uniqKey="Diez O" first="O" last="Diez">O. Diez</name></author><author><name sortKey="Izatt, L" sort="Izatt, L" uniqKey="Izatt L" first="L" last="Izatt">L. Izatt</name></author><author><name sortKey="Solomon, E" sort="Solomon, E" uniqKey="Solomon E" first="E" last="Solomon">E. Solomon</name></author><author><name sortKey="Jenkins, M" sort="Jenkins, M" uniqKey="Jenkins M" first="M" last="Jenkins">M. Jenkins</name></author><author><name sortKey="Renard, H" sort="Renard, H" uniqKey="Renard H" first="H" last="Renard">H. Renard</name></author><author><name sortKey="Hopper, J" sort="Hopper, J" uniqKey="Hopper J" first="J" last="Hopper">J. Hopper</name></author><author><name sortKey="Waring, P" sort="Waring, P" uniqKey="Waring P" first="P" last="Waring">P. Waring</name></author><author><name sortKey="Investigators, Kconfab" sort="Investigators, Kconfab" uniqKey="Investigators K" first="Kconfab" last="Investigators">Kconfab Investigators</name></author><author><name sortKey="Tavtigian, S V" sort="Tavtigian, S V" uniqKey="Tavtigian S" first="S V" last="Tavtigian">S V Tavtigian</name></author><author><name sortKey="Goldgar, D" sort="Goldgar, D" uniqKey="Goldgar D" first="D" last="Goldgar">D. Goldgar</name></author><author><name sortKey="Lindeman, G J" sort="Lindeman, G J" uniqKey="Lindeman G" first="G J" last="Lindeman">G J Lindeman</name></author><author><name sortKey="Visvader, J E" sort="Visvader, J E" uniqKey="Visvader J" first="J E" last="Visvader">J E Visvader</name></author><author><name sortKey="Couch, F J" sort="Couch, F J" uniqKey="Couch F" first="F J" last="Couch">F J Couch</name></author><author><name sortKey="Henderson, B R" sort="Henderson, B R" uniqKey="Henderson B" first="B R" last="Henderson">B R Henderson</name></author><author><name sortKey="Southey, M" sort="Southey, M" uniqKey="Southey M" first="M" last="Southey">M. Southey</name></author><author><name sortKey="Chenevix Rench, G" sort="Chenevix Rench, G" uniqKey="Chenevix Rench G" first="G" last="Chenevix-Trench">G. Chenevix-Trench</name></author><author><name sortKey="Spurdle, A B" sort="Spurdle, A B" uniqKey="Spurdle A" first="A B" last="Spurdle">A B Spurdle</name></author><author><name sortKey="Brown, M A" sort="Brown, M A" uniqKey="Brown M" first="M A" last="Brown">M A Brown</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15923272</idno><idno type="pmc">2564506</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564506</idno><idno type="RBID">PMC:2564506</idno><idno type="doi">10.1136/jmg.2005.033258</idno><date when="2005">2005</date><idno type="wicri:Area/Pmc/Corpus">000F23</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000F23</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genetic, functional, and histopathological evaluation of two C‐terminal BRCA1 missense variants</title><author><name sortKey="Lovelock, P K" sort="Lovelock, P K" uniqKey="Lovelock P" first="P K" last="Lovelock">P K Lovelock</name></author><author><name sortKey="Healey, S" sort="Healey, S" uniqKey="Healey S" first="S" last="Healey">S. Healey</name></author><author><name sortKey="Au, W" sort="Au, W" uniqKey="Au W" first="W" last="Au">W. Au</name></author><author><name sortKey="Sum, E Y M" sort="Sum, E Y M" uniqKey="Sum E" first="E Y M" last="Sum">E Y M. Sum</name></author><author><name sortKey="Tesoriero, A" sort="Tesoriero, A" uniqKey="Tesoriero A" first="A" last="Tesoriero">A. Tesoriero</name></author><author><name sortKey="Wong, E M" sort="Wong, E M" uniqKey="Wong E" first="E M" last="Wong">E M Wong</name></author><author><name sortKey="Hinson, S" sort="Hinson, S" uniqKey="Hinson S" first="S" last="Hinson">S. Hinson</name></author><author><name sortKey="Brinkworth, R" sort="Brinkworth, R" uniqKey="Brinkworth R" first="R" last="Brinkworth">R. Brinkworth</name></author><author><name sortKey="Bekessy, A" sort="Bekessy, A" uniqKey="Bekessy A" first="A" last="Bekessy">A. Bekessy</name></author><author><name sortKey="Diez, O" sort="Diez, O" uniqKey="Diez O" first="O" last="Diez">O. Diez</name></author><author><name sortKey="Izatt, L" sort="Izatt, L" uniqKey="Izatt L" first="L" last="Izatt">L. Izatt</name></author><author><name sortKey="Solomon, E" sort="Solomon, E" uniqKey="Solomon E" first="E" last="Solomon">E. Solomon</name></author><author><name sortKey="Jenkins, M" sort="Jenkins, M" uniqKey="Jenkins M" first="M" last="Jenkins">M. Jenkins</name></author><author><name sortKey="Renard, H" sort="Renard, H" uniqKey="Renard H" first="H" last="Renard">H. Renard</name></author><author><name sortKey="Hopper, J" sort="Hopper, J" uniqKey="Hopper J" first="J" last="Hopper">J. Hopper</name></author><author><name sortKey="Waring, P" sort="Waring, P" uniqKey="Waring P" first="P" last="Waring">P. Waring</name></author><author><name sortKey="Investigators, Kconfab" sort="Investigators, Kconfab" uniqKey="Investigators K" first="Kconfab" last="Investigators">Kconfab Investigators</name></author><author><name sortKey="Tavtigian, S V" sort="Tavtigian, S V" uniqKey="Tavtigian S" first="S V" last="Tavtigian">S V Tavtigian</name></author><author><name sortKey="Goldgar, D" sort="Goldgar, D" uniqKey="Goldgar D" first="D" last="Goldgar">D. Goldgar</name></author><author><name sortKey="Lindeman, G J" sort="Lindeman, G J" uniqKey="Lindeman G" first="G J" last="Lindeman">G J Lindeman</name></author><author><name sortKey="Visvader, J E" sort="Visvader, J E" uniqKey="Visvader J" first="J E" last="Visvader">J E Visvader</name></author><author><name sortKey="Couch, F J" sort="Couch, F J" uniqKey="Couch F" first="F J" last="Couch">F J Couch</name></author><author><name sortKey="Henderson, B R" sort="Henderson, B R" uniqKey="Henderson B" first="B R" last="Henderson">B R Henderson</name></author><author><name sortKey="Southey, M" sort="Southey, M" uniqKey="Southey M" first="M" last="Southey">M. Southey</name></author><author><name sortKey="Chenevix Rench, G" sort="Chenevix Rench, G" uniqKey="Chenevix Rench G" first="G" last="Chenevix-Trench">G. Chenevix-Trench</name></author><author><name sortKey="Spurdle, A B" sort="Spurdle, A B" uniqKey="Spurdle A" first="A B" last="Spurdle">A B Spurdle</name></author><author><name sortKey="Brown, M A" sort="Brown, M A" uniqKey="Brown M" first="M A" last="Brown">M A Brown</name></author></analytic><series><title level="j">Journal of Medical Genetics</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>The vast majority of <italic>BRCA1</italic> missense sequence variants remain uncharacterised for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene.</p></sec><sec><title>Objective</title><p>To elucidate the effect of two <italic>BRCA1</italic> variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in <italic>BRCA</italic> genes.</p></sec><sec><title>Methods and Results</title><p>Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype <italic>BRCA1</italic> in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with <italic>BRCA1</italic> related tumours.</p></sec><sec><title>Conclusions</title><p>A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of <italic>BRCA1</italic> unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as “benign”. In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in <italic>BRCA1</italic> and <italic>BRCA2</italic>.</p></sec></div></front></TEI><pmc article-type="case-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Med Genet</journal-id><journal-title>Journal of Medical Genetics</journal-title><issn pub-type="ppub">0022-2593</issn><issn pub-type="epub">1468-6244</issn><publisher><publisher-name>BMJ Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">15923272</article-id><article-id pub-id-type="pmc">2564506</article-id><article-id pub-id-type="publisher-id">mg33258</article-id><article-id pub-id-type="doi">10.1136/jmg.2005.033258</article-id><article-categories><subj-group subj-group-type="heading"><subject>Letter to JMG</subject></subj-group></article-categories><title-group><article-title>Genetic, functional, and histopathological evaluation of two C‐terminal BRCA1 missense variants</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lovelock</surname><given-names>P K</given-names></name></contrib><contrib contrib-type="author"><name><surname>Healey</surname><given-names>S</given-names></name></contrib><contrib contrib-type="author"><name><surname>Au</surname><given-names>W</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sum</surname><given-names>E Y M</given-names></name></contrib><contrib contrib-type="author"><name><surname>Tesoriero</surname><given-names>A</given-names></name></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>E M</given-names></name></contrib><contrib contrib-type="author"><name><surname>Hinson</surname><given-names>S</given-names></name></contrib><contrib contrib-type="author"><name><surname>Brinkworth</surname><given-names>R</given-names></name></contrib><contrib contrib-type="author"><name><surname>Bekessy</surname><given-names>A</given-names></name></contrib><contrib contrib-type="author"><name><surname>Diez</surname><given-names>O</given-names></name></contrib><contrib contrib-type="author"><name><surname>Izatt</surname><given-names>L</given-names></name></contrib><contrib contrib-type="author"><name><surname>Solomon</surname><given-names>E</given-names></name></contrib><contrib contrib-type="author"><name><surname>Jenkins</surname><given-names>M</given-names></name></contrib><contrib contrib-type="author"><name><surname>Renard</surname><given-names>H</given-names></name></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>J</given-names></name></contrib><contrib contrib-type="author"><name><surname>Waring</surname><given-names>P</given-names></name></contrib><contrib contrib-type="author"><name><surname>Investigators</surname><given-names>kConFab</given-names></name></contrib><contrib contrib-type="author"><name><surname>Tavtigian</surname><given-names>S V</given-names></name></contrib><contrib contrib-type="author"><name><surname>Goldgar</surname><given-names>D</given-names></name></contrib><contrib contrib-type="author"><name><surname>Lindeman</surname><given-names>G J</given-names></name></contrib><contrib contrib-type="author"><name><surname>Visvader</surname><given-names>J E</given-names></name></contrib><contrib contrib-type="author"><name><surname>Couch</surname><given-names>F J</given-names></name></contrib><contrib contrib-type="author"><name><surname>Henderson</surname><given-names>B R</given-names></name></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>M</given-names></name></contrib><contrib contrib-type="author"><name><surname>Chenevix‐Trench</surname><given-names>G</given-names></name></contrib><contrib contrib-type="author"><name><surname>Spurdle</surname><given-names>A B</given-names></name></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>M A</given-names></name></contrib></contrib-group><aff><bold>P K Lovelock</bold>,<bold>R Brinkworth</bold>,<bold>M A Brown</bold>, School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Australia</aff><aff><bold>P K Lovelock</bold>,<bold>S Healey</bold>,<bold>A Bekessy</bold>,<bold>G Chenevix‐Trench</bold>,<bold>A B Spurdle</bold>, Queensland Institute of Medical Research, Brisbane, Australia</aff><aff><bold>W Au</bold>,<bold>B R Henderson</bold>, Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Sydney, Australia</aff><aff><bold>E Y M Sum</bold>,<bold>G J Lindeman</bold>,<bold>J E Visvader</bold>, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia</aff><aff><bold>A Tesoriero</bold>,<bold>E M Wong</bold>,<bold>M Jenkins</bold>,<bold>J Hopper</bold>,<bold>M Southey</bold>, Department of Pathology, University of Melbourne, Melbourne, Australia</aff><aff><bold>S Hinson</bold>,<bold>F J Couch</bold>, Mayo Clinic College of Medicine, Rochester, MI, USA</aff><aff><bold>O Diez</bold>, Servei de Genetica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain</aff><aff><bold>L Izatt</bold>,<bold>E Solomon</bold>, Division of Genetics and Molecular Medicine, King's College, Guy's Hospital, London, UK</aff><aff><bold>H Renard</bold>,<bold>S V Tavtigian</bold>,<bold>D Goldgar</bold>,<bold>M Southey</bold>, International Agency for Research on Cancer, Lyon, France</aff><aff><bold>P Waring</bold>,<bold>kConFab Investigators</bold>, Peter MacCallum Cancer Centre, Melbourne, Australia</aff><author-notes><corresp>Correspondence to: Dr Georgia Chenevix‐Trench<break></break>Queensland Institute of Medical Research, Herston, Brisbane, Queensland 4000, Australia; Georgia.Trench@qimr.edu.au</corresp></author-notes><pub-date pub-type="ppub"><month>1</month><year>2006</year></pub-date><pub-date pub-type="epub"><day>2</day><month>6</month><year>2005</year></pub-date><volume>43</volume><issue>1</issue><fpage>74</fpage><lpage>83</lpage><history><date date-type="rev-recd"><day>11</day><month>5</month><year>2005</year></date><date date-type="accepted"><day>20</day><month>5</month><year>2005</year></date></history><permissions><copyright-statement>Copyright ©2006 BMJ Publishing Group Ltd.</copyright-statement></permissions><abstract><sec><title>Background</title><p>The vast majority of <italic>BRCA1</italic> missense sequence variants remain uncharacterised for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene.</p></sec><sec><title>Objective</title><p>To elucidate the effect of two <italic>BRCA1</italic> variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in <italic>BRCA</italic> genes.</p></sec><sec><title>Methods and Results</title><p>Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype <italic>BRCA1</italic> in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with <italic>BRCA1</italic> related tumours.</p></sec><sec><title>Conclusions</title><p>A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of <italic>BRCA1</italic> unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as “benign”. In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in <italic>BRCA1</italic> and <italic>BRCA2</italic>.</p></sec></abstract><kwd-group><kwd>BRCA1</kwd><kwd>functional analysis</kwd><kwd>unclassified variants</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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