title: Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.
abstract: BACKGROUND
  Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangements, and obvious splice junction mutations, is generally straightforward. However, classification of missense variants often presents a difficult problem. From a series of 20,000 full sequence tests of BRCA1 carried out at Myriad Genetic Laboratories, a total of 314 different missense changes and eight in-frame deletions were observed. Before this study, only 21 of these missense changes were classified as deleterious or suspected deleterious and 14 as neutral or of little clinical significance.
  
  
  METHODS
  We have used a combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment to classify missense variants and in-frame deletions detected during mutation screening of BRCA1.
  
  
  RESULTS
  In the present analysis we were able to classify an additional 50 missense variants and two in-frame deletions as probably deleterious and 92 missense variants as probably neutral. Thus we have tentatively classified about 50% of the unclassified missense variants observed during clinical testing of BRCA1.
  
  
  CONCLUSIONS
  An internal test of the analysis is consistent with our classification of the variants designated probably deleterious; however, we must stress that this classification is tentative and does not have sufficient independent confirmation to serve as a clinically applicable stand alone method.
authors.affiliation: Myriad Genetics, Inc, Salt Lake City, UT, 84108, USA.
authors.forename: V
authors.initials: V
authors.lastname: Abkevich
authors.forename: A
authors.initials: A
authors.lastname: Zharkikh
authors.forename: A M
authors.initials: AM
authors.lastname: Deffenbaugh
authors.forename: D
authors.initials: D
authors.lastname: Frank
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Shattuck
authors.forename: M H
authors.initials: MH
authors.lastname: Skolnick
authors.forename: A
authors.initials: A
authors.lastname: Gutin
authors.forename: S V
authors.initials: SV
authors.lastname: Tavtigian
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D019313:BRCA1 Protein / Q000145:classification / Q000235:genetics*; D002645:Chickens / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000145:classification / Q000235:genetics; D004285:Dogs; D019143:Evolution, Molecular; D029941:Fish Proteins / Q000235:genetics; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease / Q000145:classification / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D002679:Pan troglodytes / Q000235:genetics; D016415:Sequence Alignment / Q000379:methods / Q000706:statistics & numerical data; D017422:Sequence Analysis, DNA / Q000706:statistics & numerical data; D023741:Takifugu / Q000235:genetics; D029867:Xenopus Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D029941:Fish Proteins; D029867:Xenopus Proteins; D004247:DNA