Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

Lovelock, Paul K., Spurdle, Amanda B., Mok, Myth T. S., Farrugia, Daniel J., Lakhani, Sunil R., Healey, Sue, Arnold, Stephen, Buchanan, Daniel, kConFab Investigators, Couch, Fergus J., Henderson, Berik R., Goldgar, David E., Tavtigian, Sean V., Chenevix-Trench, Georgia and Brown, Melissa A (2007) Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?. Breast Cancer Research, 9 6: R82: 1-13. doi:10.1186/bcr1826

Author Lovelock, Paul K.
Spurdle, Amanda B.
Mok, Myth T. S.
Farrugia, Daniel J.
Lakhani, Sunil R.
Healey, Sue
Arnold, Stephen
Buchanan, Daniel
kConFab Investigators
Couch, Fergus J.
Henderson, Berik R.
Goldgar, David E.
Tavtigian, Sean V.
Chenevix-Trench, Georgia
Brown, Melissa A
Title Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?
Journal name Breast Cancer Research   Check publisher's open access policy
ISSN 1465-542X
Publication date 2007-11-26
Year available 2007
Sub-type Article (original research)
DOI 10.1186/bcr1826
Open Access Status DOI
Volume 9
Issue 6: R82
Start page 1
End page 13
Total pages 13
Editor B. Ponde
Place of publication United Kingdom
Publisher BioMed Central Ltd.
Collection year 2007
Language eng
Formatted abstract
Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited.

We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V.

Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification.


These data highlight the need for a range of functional studies to be performed in order to identify variants with partially compromised function. The results also raise the possibility that A1708V and R1699Q may be associated with a low or moderate risk of cancer. While data pooling strategies may provide more information for multifactorial analysis to improve the interpretation of the clinical significance of these variants, it is likely that the development of current multifactorial likelihood approaches and the consideration of alternative statistical approaches will be needed to determine whether these individually rare variants do confer a low or moderate risk of breast cancer.
Q-Index Code C1
Q-Index Status Confirmed Code

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Created: Mon, 17 Mar 2008, 11:29:52 EST by Darryl Greensill on behalf of School of Chemistry & Molecular Biosciences