A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes

Douglas F. Easton, Amie M. Deffenbaugh, Dmitry Pruss, Cynthia Frye, Richard J. Wenstrup, Kristina Allen-Brady, Sean V. Tavtigian, Alvaro N A Monteiro, Edwin S. Iversen, Fergus J Couch, David E. Goldgar

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Abstract

Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100:1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20:1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.

Original languageEnglish (US)
Pages (from-to)873-883
Number of pages11
JournalAmerican Journal of Human Genetics
Volume81
Issue number5
DOIs
StatePublished - 2007

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Neoplasm Genes
Breast Neoplasms
Mutation
Genetic Databases
Structural Models
Genetic Counseling
Pedigree
Causality
Computer Simulation
Ovarian Neoplasms
Genes
Neoplasms
Logistic Models

ASJC Scopus subject areas

  • Genetics

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A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. / Easton, Douglas F.; Deffenbaugh, Amie M.; Pruss, Dmitry; Frye, Cynthia; Wenstrup, Richard J.; Allen-Brady, Kristina; Tavtigian, Sean V.; Monteiro, Alvaro N A; Iversen, Edwin S.; Couch, Fergus J; Goldgar, David E.

In: American Journal of Human Genetics, Vol. 81, No. 5, 2007, p. 873-883.

Research output: Contribution to journalArticle

Easton, DF, Deffenbaugh, AM, Pruss, D, Frye, C, Wenstrup, RJ, Allen-Brady, K, Tavtigian, SV, Monteiro, ANA, Iversen, ES, Couch, FJ & Goldgar, DE 2007, 'A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes', American Journal of Human Genetics, vol. 81, no. 5, pp. 873-883. https://doi.org/10.1086/521032
Easton, Douglas F. ; Deffenbaugh, Amie M. ; Pruss, Dmitry ; Frye, Cynthia ; Wenstrup, Richard J. ; Allen-Brady, Kristina ; Tavtigian, Sean V. ; Monteiro, Alvaro N A ; Iversen, Edwin S. ; Couch, Fergus J ; Goldgar, David E. / A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. In: American Journal of Human Genetics. 2007 ; Vol. 81, No. 5. pp. 873-883.
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AU - Pruss, Dmitry

AU - Frye, Cynthia

AU - Wenstrup, Richard J.

AU - Allen-Brady, Kristina

AU - Tavtigian, Sean V.

AU - Monteiro, Alvaro N A

AU - Iversen, Edwin S.

AU - Couch, Fergus J

AU - Goldgar, David E.

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N2 - Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100:1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20:1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.

AB - Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100:1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20:1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.

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