Li-Fraumeni syndrome: not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis

Abstract

The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25-35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.

Keywords: Clonal hematopoiesis; Hereditary breast cancer; Li-Fraumeni syndrome; Low allele frequency; Mosaicism; Mutation; Pathogenic variant; TP53.

Fig. 1

Classic (somatic) mosaicism: The timing of post-zygotic mutation influences the distribution of mutant cells. a Mutations that occur during the first mitosis result in approximately half of the individual being affected. b Mutations that occur before left–right determination can affect both sides of the individual, including one or both gonads. c Mutations that arise after the determination of the two sides of the embryo can be confined to only one side of the individual. Only one gonad is likely to be affected. d Mutations that occur after differentiation of primordial germ cells will be absent from somatic tissues (reprinted with permission of the author [19, 20])

Fig. 2

Recommended workup for a pathogenic or likely pathogenic variant (PV) with low minor allele frequency (MAF) in TP53. a Workup to distinguish somatic mosaicism from clonal hematopoiesis (CH). b Interpretation of genetic testing results in relatives