CC BY 4.0 · AIMS Genet 2015; 02(04): 281-292
DOI: 10.3934/genet.2015.4.281
Review

Rare genetic variants: making the connection with breast cancer susceptibility

Tú Nguyen-Dumont
1   Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Victoria, 3010, Australia and The Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia
,
Jenna Stewart
1   Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Victoria, 3010, Australia and The Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia
,
Ingrid Winship
2   Department of Medicine, The University of Melbourne, Victoria, 3010, Australia and The Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia
,
Melissa C. Southey
1   Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Victoria, 3010, Australia and The Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia
› Author Affiliations

Abstract

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[1] 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?

Bona fide breast cancer predisposition gene defined as a gene in which genetic mutation(s) have validated association with breast cancer risk (of any magnitude).




Publication History

Received: 08 October 2015

Accepted: 14 December 2015

Article published online:
10 May 2021

© 2015. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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