PM2_Supporting is met: NM_000546.6:c.293C>G (p.Pro98Arg) is absent from gnomAD v2.1 and v4.1 (0 alleles across all populations), satisfying the VCEP PM2_Supporting threshold of allele frequency <0.00003.

PP3_Moderate is met: The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G. This variant has aGVGD Class C65 and BayesDel score 0.591769 (≥0.16), with no predicted splicing impact (SpliceAI max delta 0.00). REVEL score of 0.955 provides additional in silico support.

PVS1 is not applicable: this is a missense variant; the TP53 VCEP reserves PVS1 for null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletions).

PS3 and BS3 are not met: the VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg. Kato class is 'Partially functional' and Giacomelli reports 'noLOF', which does not satisfy VCEP PS3 or BS3 criteria thresholds.

PM1 is not met: codon 98 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282), and the residue is not a statistically significant hotspot on cancerhotspots.org. PM5 is not met: no other Pro98 missense variant has a VCEP P/LP classification.

PS1, PS2, PS4, PP1, PP4, BA1, BS1, BS2, BS3, BS4, BP4 are not met based on absence of qualifying evidence from ClinVar, gnomAD, published literature, and VCEP reference data.

PP5, BP1, BP2, BP5, BP6, PM6, PP2, and BP3 are not applicable under the TP53 VCEP v2.4.0 specifications. PS5 is not included in the VCEP criteria set. BP7 is not applicable as this is a missense variant.

Tavtigian point tally: PM2_Supporting (+1) + PP3_Moderate (+2) = 3 points. Per TP53 VCEP v2.4.0 ranges: ≥10 Pathogenic, 6-9 Likely Pathogenic, -1 to 5 Uncertain Significance, -6 to -2 Likely Benign, ≤-7 Benign. Total of 3 points classifies this variant as Uncertain Significance (VUS).