Rare genetic variants: making the connection with breast cancer susceptibility

Tu Nguyen-Dumont, Jenna Stewart, Ingrid M. Winship, Melissa Caroline Southey

Research output: Contribution to journalReview ArticleOtherpeer-review


The practice of clinical genetics in the context of breast cancer predisposition has reached another critical point in its evolution. For the past two decades, genetic testing offered to women attending clinics has been limited to BRCA1 and BRCA2 unless other syndromic indicators have been evident (e.g. PTEN and TP53 for Cowden and Li-Fraumeni syndrome, respectively). Women (and their families) who are concerned about their personal and/or family history of breast and ovarian cancer have enthusiastically engaged with clinical genetics services, anticipating a genetic cause for their cancer predisposition will be identified and to receive clinical guidance for their risk management and treatment options. Genetic testing laboratories have demonstrated similar enthusiasm for transitioning from single gene to gene panel testing that now provide opportunities for the large number of women found not to carry mutations in BRCA1 and BRCA2, enabling them to undergo additional genetic testing. However, these panel tests have limited clinical utility until more is understood about the cancer risks (if any) associated with the genetic variation observed in the genes included on these panels. New data is urgently needed to improve the interpretation of the genetic variation data that is already reported from these panels and to inform the selection of genes included in gene panel tests in the future. To address this issue, large internationally coordinated research studies are required to provide the evidence-base from which clinical genetics for breast cancer susceptibility can be practiced in the era of gene panel testing and oncogenetic practice.
Two significant steps associated with this process include i) validating the genes on these panels (and those likely to be added in the future) as bona fide breast cancer predisposition genes and ii) interpreting the variation, on a variant-by-variant basis in terms of their likely “pathogenicity” ― a process commonly referred to as “variant classification” that will enable this new genetic information to be used at an individual level in clinical genetics services. Neither of these fundamental steps have been achieved for the majority of genes included on the panels.
We are thus at a critical point for translational research in breast cancer clinical genetics ― how can rare genetic variants be interpreted such that they can be used in clinical genetics services and oncogenetic practice to identify and to inform the management of families that carry these variants?
Original languageEnglish
Pages (from-to)281-292
Number of pages12
JournalAIMS Genetics
Issue number4
Publication statusPublished - 21 Dec 2015
Externally publishedYes


  • rare variants
  • breast cancer
  • clinical genetics
  • clinical translation
  • in silico prediction

Cite this