The NM_000546.6: c.314G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 105 (p.Gly105Asp). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors). This variant has been reported in 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID:38714106, Internal lab contributor). This variant has an allele frequency of 6.201e-7 (1/1612526 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 vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 39774325, 29979965, 30224644). Computational predictor scores (BayesDel = 0.568262; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has 4 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_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: PS4_Supporting, PP4_Moderate, PM2_Supporting, PP3_Moderate, PM1_Supporting. (Bayesian Points: 7; VCEP specifications version 2.4)