Article Text

other Versions

PDF
Short report
Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes
  1. Mohammad R Akbari1,
  2. Shiyu Zhang1,
  3. Isabel Fan2,
  4. Robert Royer1,
  5. Song Li1,
  6. Harvey Risch3,
  7. John McLaughlin2,
  8. Barry Rosen4,
  9. Ping Sun1,
  10. Steven A Narod1
  1. 1Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada
  2. 2Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada
  3. 3Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA
  4. 4Department of Gynecology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Steven A Narod, Women's College Research Institute, University of Toronto, 790 Bay Street, Toronto, ON, Canada M5G 1N8; steven.narod{at}wchospital.ca

Abstract

Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, p<10−4). In contrast, the cumulative risk of cancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives.

  • Cancer: breast
  • genetic epidemiology
  • dermatology
  • molecular genetics
  • prevention
  • clinical genetics
  • genetic screening/counselling

Statistics from Altmetric.com

Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Women's College Research Institute, University of Toronto.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.