RT Journal Article
SR Electronic
T1 Classification of <em>BRCA1</em> missense variants of unknown clinical significance
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 138
OP 146
DO 10.1136/jmg.2004.024711
VO 42
IS 2
A1 C M Phelan
A1 V Đapić
A1 B Tice
A1 R Favis
A1 E Kwan
A1 F Barany
A1 S Manoukian
A1 P Radice
A1 R B van der Luijt
A1 B P M van Nesselrooij
A1 G Chenevix-Trench
A1 T Caldes
A1 M de La Hoya
A1 S Lindquist
A1 S V Tavtigian
A1 D Goldgar
A1 Å Borg
A1 S A Narod
A1 A N A Monteiro
YR 2005
UL http://jmg.bmj.com/content/42/2/138.abstract
AB Background:BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast–ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. Objective: To investigate a panel of missense variants. Methods and results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396–1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated. Conclusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.