Kratz CP, Freycon C, Maxwell KN, et al. - Researchers sought to describe the phenotypic spectrum of Li-Fraumeni syndrome and conduct phenotype-genotype correlations across the phenotypic spectrum.

• The germline variant data set of the International Agency for Research on Cancer TP53 database that accommodates data on a cohort of 3,034 persons from 1,282 families were analyzed and classified.

• The term Li-Fraumeni spectrum involved (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer who does not meet Li-Fraumeni syndrome testing criteria; and (4) incidental Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer.

• Patients who met vs those who did not meet Li-Fraumeni syndrome testing criteria differed meaningfully in the TP53 variant distribution.

• There were significant differences in tumor spectra, with patients who met Li-Fraumeni syndrome genetic testing criteria (n = 2,139) having more early adrenal, brain, connective tissue, and bone tumors.

• There were more breast and other cancers among carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678); 45% of these occurred after age 45 years. Both groups had the presence of hotspot variants.

• Patients with Li-Fraumeni syndrome exclusively exhibit several variants, while patients with attenuated Li-Fraumeni syndrome exclusively exhibit other variants.

• Most TP53 variants in patients who met Li-Fraumeni syndrome genetic testing criteria were classified as pathogenic/likely pathogenic (1,757 of 2,139, 82.2%), whereas in patients who did not meet the Li-Fraumeni syndrome genetic testing criteria, 40.4% (404 of 678) of identified TP53 variants were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown.

• The new classification, Li-Fraumeni spectrum, is suggested to be a step toward attaining insight into the factors that result in phenotypic disparities and may serve as a model for other cancer predisposition syndromes.