NM_000546.6:c.-29+121G>T is a deep intronic substitution in intron 1 of TP53, 121 nucleotides downstream of the exon 1 splice donor (c.-29). This variant falls outside all canonical null-variant categories (PVS1 not applicable) and does not alter the amino acid sequence (PS1, PM1, PM5 not applicable).¹ The variant is absent from gnomAD v2.1 and v4.1 (0 alleles across >1.6 million individuals). This absence meets the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%). However, caution is warranted as deep intronic regions may have reduced coverage in exome sequencing data.² SpliceAI predicts no splicing impact (max delta score = 0.00). No cryptic splice site creation or disruption is predicted. This supports a benign interpretation through two independent TP53 VCEP criteria: BP4_Supporting (computational evidence, SpliceAI ≤ 0.1 for intronic variants outside ±1,2) and BP7_Supporting (intronic variant at +121, beyond +7, with no predicted splicing aberration).³ No functional studies, de novo observations, co-segregation data, case-control studies, or ClinVar submissions have been reported for this variant. It is absent from COSMIC and all TP53 locus-specific databases. Multiple pathogenic criteria (PS2, PS3, PS4, PP1, PP4) and benign criteria (BS1, BS2, BS3, BS4, BA1) cannot be assessed due to complete absence of variant-specific clinical or experimental data.⁴ Under the TP53 VCEP v2.4.0 Tavtigian point-based framework, the applied criteria yield: PM2_Supporting (+1 point), BP4_Supporting (-1 point), BP7_Supporting (-1 point). Total = -1 point, which maps to Uncertain Significance (range -1 to +5). However, the VCEP caveat states that a final point value of -1 may be overridden to Likely Benign when at least 2 benign evidence codes are applied AND PM2_Supporting is the only pathogenic code. Both conditions are met here, resulting in a final classification of Likely Benign.⁵