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Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics

Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics
Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics
Objectives: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. Design: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. Results: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p < 0.05) than all models except BRCAPRO ( area under the receiver operating characteristic curve statistics: BOADICEA=0.77, BRCAPRO=0.76, IBIS=0.74, Manchester=0.75, Myriad=0.72). All models under-predicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. Conclusions: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.
models, susceptibility, breast, risk, estrogen-receptor, cancer, individuals, brca2, mutations, brca1, prevalence, gene, ovarian-cancer, breast-cancer, carrier probabilities
0022-2593
425-431
Antoniou, A.C.
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Hardy, R.
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Walker, L.
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Evans, D.G.
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Shenton, A.
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Eeles, R.
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Shanley, S.
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Pichert, G.
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Izatt, L.
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Rose, S.
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Douglas, F.
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Eccles, D.
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Morrison, P.J.
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Scott, J.
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Zimmern, R.L.
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Easton, D.F.
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Pharoah, P.D.P.
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Antoniou, A.C.
6dc040a0-bd30-4178-995b-ca6f237949e1
Hardy, R.
b3f0f66e-4cda-4e9a-aca1-955f7ecdd132
Walker, L.
99ada328-aeda-4264-8fc8-3154e2090265
Evans, D.G.
b58c99fc-4da0-4d7e-b140-f22307befe5e
Shenton, A.
fd74c39a-da08-4ea0-943a-f67f7c79205b
Eeles, R.
c7ae2359-6f49-4f42-88f8-a241570f9d4f
Shanley, S.
8015c790-26c1-4697-8632-be90203bddde
Pichert, G.
2bdde7cf-ac04-416f-b820-b0a833e6191f
Izatt, L.
5cabcdef-374a-4441-b571-9c7b1665b720
Rose, S.
232c2464-efc4-4b5b-a199-4f554a33b3c2
Douglas, F.
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Eccles, D.
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Morrison, P.J.
cdcdba90-397b-4345-b409-7e2d1e1282d4
Scott, J.
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Zimmern, R.L.
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Easton, D.F.
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Pharoah, P.D.P.
72233519-0a97-430d-9b68-267585ca7cb7

Antoniou, A.C., Hardy, R., Walker, L., Evans, D.G., Shenton, A., Eeles, R., Shanley, S., Pichert, G., Izatt, L., Rose, S., Douglas, F., Eccles, D., Morrison, P.J., Scott, J., Zimmern, R.L., Easton, D.F. and Pharoah, P.D.P. (2008) Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. Journal of Medical Genetics, 45 (7), 425-431. (doi:10.1136/jmg.2007.056556).

Record type: Article

Abstract

Objectives: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. Design: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. Results: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p < 0.05) than all models except BRCAPRO ( area under the receiver operating characteristic curve statistics: BOADICEA=0.77, BRCAPRO=0.76, IBIS=0.74, Manchester=0.75, Myriad=0.72). All models under-predicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. Conclusions: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.

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Published date: July 2008
Keywords: models, susceptibility, breast, risk, estrogen-receptor, cancer, individuals, brca2, mutations, brca1, prevalence, gene, ovarian-cancer, breast-cancer, carrier probabilities

Identifiers

Local EPrints ID: 62673
URI: https://eprints.soton.ac.uk/id/eprint/62673
ISSN: 0022-2593
PURE UUID: 331fe4c0-4bc0-48d5-9db5-ed053de17ad2

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Date deposited: 16 Mar 2009
Last modified: 13 Mar 2019 20:27

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Contributors

Author: A.C. Antoniou
Author: R. Hardy
Author: L. Walker
Author: D.G. Evans
Author: A. Shenton
Author: R. Eeles
Author: S. Shanley
Author: G. Pichert
Author: L. Izatt
Author: S. Rose
Author: F. Douglas
Author: D. Eccles
Author: P.J. Morrison
Author: J. Scott
Author: R.L. Zimmern
Author: D.F. Easton
Author: P.D.P. Pharoah

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