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Classification of BRCA1 missense variants of unknown clinical significance

Author:
  • 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
Publishing year: 2005
Language: English
Pages: 138-146
Publication/Series: Journal of Medical Genetics
Volume: 42
Issue: 2
Document type: Journal article
Publisher: BMJ Publishing Group

Abstract english

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.

Keywords

  • Medical Genetics

Other

Published
  • ISSN: 0022-2593
Åke Borg
Åke Borg
E-mail: ake [dot] borg [at] med [dot] lu [dot] se

Principal investigator

Oncology and Pathology, MV

+46 46 275 25 52

MV 404 C21B2

90

Project manager

Familial Breast Cancer

90

Professor

Oncology and Pathology, MV

MV 404 C21C2

90