Clinical implications of rare and common variation in preimplantation genetic testing for breast cancer

Recently, some clinics have begun using preimplantation genetic testing for monogenic disorders (PGT-M) for moderately penetrant breast cancer (BC) risk variants, while other clinics use polygenic risk scores (PRS) in the context of preimplantation embryo screening. Using both simulation and formal mathematical approaches, we evaluated: 1) in what circumstances embryo selection using PRS could lead to systematically erroneous results due to failure to consider monogenic carrier status; and 2) whether PGT-M for moderate penetrance variants could lead to erroneous results due to unassessed, yet elevated PRS. Variants in BRCA1, BRCA2 , and PALB2 resulted in a risk distribution that was essentially disjoint from the non-carriers, regardless of PRS. By contrast, for moderately penetrant genes, standard PGT-M would fail to select the lowest risk embryo approximately 5% of the time due to elevated PRS. This complex interplay suggests that caution should be exercised when considering preimplantation genetic testing involving exclusively monogenic variants of moderate penetrance or polygenic scores.