Are women with pathogenic variants in PMS2 and MSH6 really at high lifetime risk of breast cancer?

Abstract

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.