Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis

Marcelo A. Carvalho, Sylvia M. Marsillac, Rachel Karchin, Siranoush Manoukian, Scott Grist, Ramona F. Swaby, Turan P. Urmenyi, Edson Rondinelli, Rosane Silva, Luis Gayol, Lisa Baumbach, Rebecca Sutphen, Jennifer L. Pickard-Brzosowicz, Katherine L. Nathanson, Andrej Sali, David Goldgar, Fergus J Couch, Paolo Radice, Alvaro N A Monteiro

Research output: Contribution to journalArticle

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Abstract

Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with <45% of wild-type activity can be classified as deleterious whereas variants with >50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability.

Original languageEnglish (US)
Pages (from-to)1494-1501
Number of pages8
JournalCancer Research
Volume67
Issue number4
DOIs
StatePublished - Feb 15 2007

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Germ Cells
Germ-Line Mutation
Ovarian Neoplasms
Transcriptional Activation
Meta-Analysis
Neoplasms
Proteins
Breast Neoplasms
Sensitivity and Specificity
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carvalho, M. A., Marsillac, S. M., Karchin, R., Manoukian, S., Grist, S., Swaby, R. F., ... Monteiro, A. N. A. (2007). Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Research, 67(4), 1494-1501. https://doi.org/10.1158/0008-5472.CAN-06-3297

Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. / Carvalho, Marcelo A.; Marsillac, Sylvia M.; Karchin, Rachel; Manoukian, Siranoush; Grist, Scott; Swaby, Ramona F.; Urmenyi, Turan P.; Rondinelli, Edson; Silva, Rosane; Gayol, Luis; Baumbach, Lisa; Sutphen, Rebecca; Pickard-Brzosowicz, Jennifer L.; Nathanson, Katherine L.; Sali, Andrej; Goldgar, David; Couch, Fergus J; Radice, Paolo; Monteiro, Alvaro N A.

In: Cancer Research, Vol. 67, No. 4, 15.02.2007, p. 1494-1501.

Research output: Contribution to journalArticle

Carvalho, MA, Marsillac, SM, Karchin, R, Manoukian, S, Grist, S, Swaby, RF, Urmenyi, TP, Rondinelli, E, Silva, R, Gayol, L, Baumbach, L, Sutphen, R, Pickard-Brzosowicz, JL, Nathanson, KL, Sali, A, Goldgar, D, Couch, FJ, Radice, P & Monteiro, ANA 2007, 'Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis', Cancer Research, vol. 67, no. 4, pp. 1494-1501. https://doi.org/10.1158/0008-5472.CAN-06-3297
Carvalho MA, Marsillac SM, Karchin R, Manoukian S, Grist S, Swaby RF et al. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Research. 2007 Feb 15;67(4):1494-1501. https://doi.org/10.1158/0008-5472.CAN-06-3297
Carvalho, Marcelo A. ; Marsillac, Sylvia M. ; Karchin, Rachel ; Manoukian, Siranoush ; Grist, Scott ; Swaby, Ramona F. ; Urmenyi, Turan P. ; Rondinelli, Edson ; Silva, Rosane ; Gayol, Luis ; Baumbach, Lisa ; Sutphen, Rebecca ; Pickard-Brzosowicz, Jennifer L. ; Nathanson, Katherine L. ; Sali, Andrej ; Goldgar, David ; Couch, Fergus J ; Radice, Paolo ; Monteiro, Alvaro N A. / Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. In: Cancer Research. 2007 ; Vol. 67, No. 4. pp. 1494-1501.
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