Classification of BRCA1 missense variants of unknown clinical significance

C M Phelan, V Dapic, B Tice, R Favis, E Kwan, F Barany, S Manoukian, P Radice, R B van der Luijt, B P M van Nesselrooij, G Chenevix-Trench, T Caldes, M de La Hoya, S Lindquist, S V Tavtigian, D Goldgar, Åke Borg, S A Narod, A N A Monteiro

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)138-146
JournalJournal of Medical Genetics
Issue number2
Publication statusPublished - 2005

Subject classification (UKÄ)

  • Medical Genetics


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