We have read the recent paper by Roberts et al. in Genetics in Medicine with great interest. 1 In this paper the authors claim that MSH6 and PMS2 germline pathogenic variants are associated with increased breast cancer risk. The authors are to be commended for analyzing all MMR genes in a single study and performing gene-stratified analyses. They report a strong increase in cumulative risk of breast cancer for MSH6-and PMS2-associated Lynch syndrome patients (31.1 and 37.7% at age 60 respectively). If confirmed this would have major consequences for surveillance policy in this subset of Lynch patients. Nonetheless, we would like to place some notes on the interpretation of the results.

Risk analyses in clinically selected cohorts should be interpreted with caution because they are influenced by ascertainment and testing bias. We have previously reported on the cancer spectrum in PMS2 families as well and we too found an increased standardized incidence ratio (SIR) for breast cancer of 3.8 (95% CI: 1.9–6.8). 2 However, although we corrected colorectal cancer and endometrial cancer risk estimates for ascertainment bias using modified segregation analyses, event rates were too low to apply the same corrections for other cancers, including breast cancer. Therefore, SIR analyses were presented, but with appropriate skepticism. Roberts et al. suggest that ascertainment bias in their study is counteracted by inclusion of patients not only selected due to a clinical suspicion of Lynch syndrome, but also because of other cancer prevalence in the proband or family. However, the inclusion of these patients might have actually resulted in overestimation of the breast cancer association.