The NM_000546.6 c.1146del (p.Lys382AsnfsTer?) is a TP53 frameshift variant inducing a stop codon read-through. The variant is predicted to escape nonsense mediated decay, targeting a region of unknown function representing <10% of the protein and introducing a C-terminal extension of 28 residues in the protein (PVS1_Moderate). This variant has been reported in 3 unrelated families meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal lab contributors). This variant has an allele frequency of 6.196e-7 (1/1614052 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1_Moderate, PS4_Moderate, PP1, PM2_Supporting. (Bayesian Points: 6; VCEP specifications version 2.3)