NM_000546.5:c.422G>A (p.Cys141Tyr) is a missense variant in exon 5 of TP53. This variant is extremely rare in population databases: gnomAD v4.1 total allele frequency = 1.86e-6 (3/1,614,148 alleles), meeting PM2_Supporting (VCEP threshold <0.00003). It is absent from gnomAD v2.1 and gnomAD-Canada.¹ Functional studies demonstrate complete loss of function. The variant is non-functional in the Kato transactivation assay, and all additional eligible assays (Funk, Giacomelli, Kotler) show LOF, satisfying PS3 (strong) per TP53 VCEP specifications.² In silico predictions strongly support a deleterious effect: BayesDel score = 0.568676, aGVGD Class C65, REVEL = 0.897. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.422G>A.³ SpliceAI predicts no splicing impact (max delta = 0.00), confirming this variant is assessed as a missense change without splicing aberration.⁴ The variant has been reported in ClinVar as Pathogenic by 5 clinical laboratories and Likely Pathogenic by 2, and has been observed 182 times in COSMIC somatic cancer database.⁵ Combined Tavtigian point score (TP53 VCEP v2.4.0): PS3 (strong) = +4, PP3_moderate = +2, PM2_Supporting = +1. Total = +7 points, which falls in the Likely Pathogenic range (6-9 points).⁶ Additional criteria (PS4, PS2, PP1) could not be assessed due to lack of proband-level cancer phenotype data, de novo observations, and cosegregation data in the available evidence. If PS4 evidence becomes available with ≥4 points (≥1 proband with strongly associated LFS cancer), the total would reach ≥10 points, reclassifying the variant as Pathogenic.