We read with some concern the recent article in Genetics in Medicine reporting a high lifetime risk of breast cancer in pathogenic variant (PV) carriers for PMS2 and MSH6 (ref. 1). Although the reported odds ratios for breast cancer were given as MSH6 (2.11; 95% confidence interval [CI]= 1.56–2.86) and PMS2 (2.92; 95% CI= 2.17–3.92) the cumulative risks to age 60 were given as 31.1%(95% CI, 21.9–40.7) and 37.7%(95% CI, 27.5–47.8) respectively. These are equivalent to UK National Institute for Health and Care Excellence (NICE) defined high lifetime risks. These two analyses are inaccurate given that the risk of breast cancer to the age of 60 years in the UK and United States is 5–6%. Therefore, if the risks from incidence ratios and Kaplan–Meier were equivalent, the odds ratios would be over 6-fold for PMS2 and> 5-fold for MSH6. The most meaningful unbiased risks are likely to come from prospective analysis. The cumulative risk to age 70 years in 124 PMS2 PV carriers was shown to be only 8.6% to age 70 years in the largest such analysis undertaken thus far. 2 A single case between 70 and 75 years gave a distorted nonsignificant increased risk. For MSH6 the cumulative risk to age 75 years was 13.3%(95% CI= 2.2–24.4) odds ratio 1.4 (95% CI= 0.2–2.6). As such the upper confidence interval at age 75 years for MSH6 rules out the cumulative risks provided by the GeneDx study. 1

The huge discrepancy observed may be attributed to a number of issues. First is the lack of adjustment of the clear ascertainment bias in contrast with the majority of published reports of cumulative risk of breast cancer in patients with tumor suppressor gene variants. Second is the absence of information on the proportion of women who were tested who had a breast cancer diagnosis. An earlier report from this group reported 5209/9276 (56.2%) of all referred samples had breast cancer. 3 If the proportion remains constant, a huge bias is present that precludes any comparison of incidence ratios with the general population. Third, the authors “compound the felony” with the inappropriate use of Kaplan–Meier analyses for cumulative risks. Despite the fact the authors report an odds ratio of below 1 for MLH1, they then report a 15.5%(95% CI= 5.5–30.2) risk of breast cancer by age 60 years. This is equivalent to a threefold excess risk. It is therefore highly likely that if the authors had carried out