Genetic and Histopathologic Evaluation of BRCA1 and BRCA2 DNA Sequence Variance of Unknown Clinical Significance

Chenevix-Trench, Georgia, Healey, Sue, Lakhani, Sunil, Waring, Paul, Cummings, Margaret, Brinkworth, Ross, Deffenbaugh, Amie M., Burbidge, Lynn Anne, Pruss, Dmitry, Judkins, Thad, Scholl, Tom, Bekessy, Anna, Marsh, Anna, Lovelock, Paul, Wong, Ming, Tesoriero, Andrea, Renard, Helene, Southey, Melissa, Hopper, John L., Yannoukakos, Koulis, Brown, Melissa, kConFab Investigators, Easton, Douglas, Tavtigian, Sean V., Goldgar, David and Spurdle, Amanda B. (2006) Genetic and Histopathologic Evaluation of BRCA1 and BRCA2 DNA Sequence Variance of Unknown Clinical Significance. Cancer Research, 66 4: 2019-2027. doi:10.1158/0008-5472.CAN-05-3546

Author Chenevix-Trench, Georgia
Healey, Sue
Lakhani, Sunil
Waring, Paul
Cummings, Margaret
Brinkworth, Ross
Deffenbaugh, Amie M.
Burbidge, Lynn Anne
Pruss, Dmitry
Judkins, Thad
Scholl, Tom
Bekessy, Anna
Marsh, Anna
Lovelock, Paul
Wong, Ming
Tesoriero, Andrea
Renard, Helene
Southey, Melissa
Hopper, John L.
Yannoukakos, Koulis
Brown, Melissa
kConFab Investigators
Easton, Douglas
Tavtigian, Sean V.
Goldgar, David
Spurdle, Amanda B.
Title Genetic and Histopathologic Evaluation of BRCA1 and BRCA2 DNA Sequence Variance of Unknown Clinical Significance
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2006-02-15
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-05-3546
Volume 66
Issue 4
Start page 2019
End page 2027
Total pages 9
Editor F. J. Rauscher III
Place of publication Philadelphia, P. A.
Publisher American Association for Cancer Research
Language eng
Subject 270201 Gene Expression
270202 Genome Structure
321015 Oncology and Carcinogenesis
Abstract Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that similar to 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants.
Keyword Oncology
Exonic Splicing Enhancers
Familial Breast-cancer
Missense Mutations
Unclassified Variants
Product Brca1
Repeat Region
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
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