Advanced

Classification of BRCA1 missense variants of unknown clinical significance

Phelan, C M; Dapic, V; Tice, B; Favis, R; Kwan, E; Barany, F; Manoukian, S; Radice, P; van der Luijt, R B and van Nesselrooij, B P M, et al. (2005) In Journal of Medical Genetics 42(2). p.138-146
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medical Genetics
volume
42
issue
2
pages
138 - 146
publisher
BMJ Publishing Group
external identifiers
  • wos:000226748100008
  • pmid:15689452
  • scopus:13444292150
ISSN
0022-2593
DOI
10.1136/jmg.2004.024711
language
English
LU publication?
yes
id
0115a779-e7d6-44d0-93a6-cf3685438c61 (old id 254324)
date added to LUP
2007-08-07 17:22:33
date last changed
2017-08-20 04:14:58
@article{0115a779-e7d6-44d0-93a6-cf3685438c61,
  abstract     = {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.},
  author       = {Phelan, C M and Dapic, V and Tice, B and Favis, R and Kwan, E and Barany, F and Manoukian, S and Radice, P and van der Luijt, R B and van Nesselrooij, B P M and Chenevix-Trench, G and Caldes, T and de La Hoya, M and Lindquist, S and Tavtigian, S V and Goldgar, D and Borg, Åke and Narod, S A and Monteiro, A N A},
  issn         = {0022-2593},
  language     = {eng},
  number       = {2},
  pages        = {138--146},
  publisher    = {BMJ Publishing Group},
  series       = {Journal of Medical Genetics},
  title        = {Classification of BRCA1 missense variants of unknown clinical significance},
  url          = {http://dx.doi.org/10.1136/jmg.2004.024711},
  volume       = {42},
  year         = {2005},
}