title: Classification of BRCA1 missense variants of unknown clinical significance.
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.
  
  
  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.
authors.affiliation: H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. monteian@moffitt.usf.edu.
authors.forename: C M
authors.initials: CM
authors.lastname: Phelan
authors.forename: V
authors.initials: V
authors.lastname: Dapic
authors.forename: B
authors.initials: B
authors.lastname: Tice
authors.forename: R
authors.initials: R
authors.lastname: Favis
authors.forename: E
authors.initials: E
authors.lastname: Kwan
authors.forename: F
authors.initials: F
authors.lastname: Barany
authors.forename: S
authors.initials: S
authors.lastname: Manoukian
authors.forename: P
authors.initials: P
authors.lastname: Radice
authors.forename: R B
authors.initials: RB
authors.lastname: van der Luijt
authors.forename: B P M
authors.initials: BP
authors.lastname: van Nesselrooij
authors.forename: G
authors.initials: G
authors.lastname: Chenevix-Trench
authors.lastname: kConFab
authors.forename: T
authors.initials: T
authors.lastname: Caldes
authors.forename: M
authors.initials: M
authors.lastname: de la Hoya
authors.forename: S
authors.initials: S
authors.lastname: Lindquist
authors.forename: S V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: D
authors.initials: D
authors.lastname: Goldgar
authors.forename: A
authors.initials: A
authors.lastname: Borg
authors.forename: S A
authors.initials: SA
authors.lastname: Narod
authors.forename: A N A
authors.initials: AN
authors.lastname: Monteiro
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019313:BRCA1 Protein / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation
chemical_list: D019313:BRCA1 Protein