title: Assessing biases of information contained in pedigrees for the classification of BRCA-genetic variants: a study arising from the ENIGMA analytical working group.
abstract: OBJECTIVE
  One way of evaluating family history (FH) for classifying BRCA1/2 variants of uncertain clinical significance (VUS) is to assess the "BRCA-ness" of a pedigree by comparing it to reference populations. The aim of this study was to assess if prediction of BRCA pathogenic variant (mutation) status based on pedigree information differed due to changes in FH since intake, both in families with a pathogenic variant (BRCAm) and in families with wild-type (BRCAwt).
  
  
  METHODS
  We compared the BRCA1/2 pathogenic variant detection probabilities between intake and most recent pedigree for BRCAm families (n = 64) and BRCAwt (n = 118) using the BRCAPRO software program.
  
  
  RESULTS
  Follow-up time between intake and most recent pedigree was significantly longer (p < 0.001) in the BRCAm compared to the BRCAwt families. Among BRCAwt families, the probability to detect a pathogenic variant did not change over time. Conversely, among the BRCAm, this probability was significantly higher for most recent vs. intake pedigree (p = 0.006).
  
  
  CONCLUSIONS
  Clinical scores change significantly over time for BRCAm families. This may be due to differences in follow-up, but also to differences in cancer risks from carrying a pathogenic variant in a highly penetrant gene. To reduce bias, models for VUS classification should incorporate FH collected at intake.
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: C H H
authors.initials: CH
authors.lastname: Kerkhofs
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: A B
authors.initials: AB
authors.lastname: Spurdle
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lindsey
authors.affiliation: Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Goldgar
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: E B
authors.initials: EB
authors.lastname: Gómez-García
keywords: BRCA1/2; Family history; Intake pedigrees; Variant classification models; Variants of uncertain clinical significance