title: A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history.
abstract: BACKGROUND
  Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs.
  
  
  METHODS
  We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families).
  
  
  RESULTS
  The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain.
  
  
  CONCLUSIONS
  The present study shows that these developed models are useful to classify UVs in clinical genetic practice.
authors.affiliation: Department of Clinical Genetics, University Hospital Maastricht, Maastricht, the Netherlands. Encarna.Gomezgarcia@gen.unimaas.nl
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gómez García
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
authors.forename: Maarten
authors.initials: M
authors.lastname: Timmermans
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Rogier
authors.initials: R
authors.lastname: Oldenburg
authors.forename: Senno
authors.initials: S
authors.lastname: Verhoef
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Dommering
authors.forename: Margreet G E M
authors.initials: MG
authors.lastname: Ausems
authors.forename: Theo A M
authors.initials: TA
authors.lastname: van Os
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van der Hout
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Ligtenberg
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Rob B
authors.initials: RB
authors.lastname: van der Luijt
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Jan J P
authors.initials: JJ
authors.lastname: Gille
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lindsey
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Marinus J
authors.initials: MJ
authors.lastname: Blok
authors.forename: Maaike P G
authors.initials: MP
authors.lastname: Vreeswijk
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D010051:Ovarian Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis; D012372:ROC Curve
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein