The prediction of breast-cancer risk and the risk of genetic overdiagnosis

Limiting genetic tests for breast cancer susceptibility

A leading oncogeneticist warns against the risk of “genetic over-diagnosis” on the basis of spurious genetic tests and proposes limiting testing to clinically validated genes.

Screening for genes whose risk association with breast cancer has yet to be proven is not justified and potentially harmful, argue an international team of leading geneticists and oncologists in a paper published this week in the New England Journal of Medicine: Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk.


We have discussed some of the difficulties of assigning risk to rare variants and reviewed the genes for which the evidence of association with breast cancer is sufficiently robust to be incorporated into personalized risk prediction. Variants that are predicted to truncate BRCA1 and BRCA2 (together with a subset of missense variants) confer a high risk of breast cancer; PALB2 and perhaps PTEN may also fall in this category, but the evidence is insufficient to place them confidently in the category of high risk rather than moderate risk. For TP53, both missense and protein-truncating variants are associated with substantially increased risks of breast cancer. Genes that fall into the category of moderate risk (for which fully deleterious mutations confer a risk of breast cancer that is two to four times as high as that in the general population) include CHEK2, ATM, and NF1. There is clear evidence for an association with risk of cancer for STK11, CDH1, and NBN, but the risk estimates are too imprecise for categorization. Estimates of risk for PTEN, STK11, and CDH1 are derived entirely from studies of selected patients identified through specialized clinics and may be seriously overestimated. We found insufficient evidence to establish any other genes as conferring a predisposition for breast cancer and would caution against their use in the prediction of breast-cancer risk. As the costs of sequencing decline, it is inevitable that the use of gene-panel testing, and indeed whole-exome and whole-genome sequencing, will become widespread. Therefore, there is an urgent need for much larger, well-designed population- and family-based studies in diverse populations that will provide reliable estimates of risk for the purpose of counseling. The systematic collection of data from ongoing use of panel testing linked to the epidemiologic and clinical data may also make an important contribution. Other genes that convey susceptibility to breast cancer (and perhaps rarer variants in noncoding sequences) will probably be identified and may be added to genetic-testing panels. Panel testing can make a useful contribution to prediction of a woman’s risk of breast cancer, but end users need to be aware of the limitations of these panels.

  • Read Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk, nejm, June 4, 2015.
  • Read Limiting genetic tests for breast cancer susceptibilityMcGill News, 1 JUN 2015.

2 thoughts on “The prediction of breast-cancer risk and the risk of genetic overdiagnosis”

Have your say! Share your views