NM_000546.5(NP_000537.3):c.370T>C (p.Cys124Arg) is a missense variant in exon 4 of TP53.
This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2_Supporting per TP53 VCEP v2.4.0 (allele frequency <0.003%).
gnomad_v2 ↗ gnomad_v4 ↗Functional studies demonstrate that p.Cys124Arg is non-functional in the Kato et al. assay and exhibits loss of function in the majority of other eligible assays (Giacomelli, Kotler), meeting PS3 at strong strength per TP53 VCEP specifications (Functional-worksheet.xlsx, Supplementary Table S3).
In silico predictors support a deleterious effect: aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, meeting PP3 at moderate strength per TP53 VCEP specifications (PP3-BP4-codes.xlsx, Supplementary Table S2). SpliceAI predicts no splicing impact (max delta 0.02).
spliceai ↗The variant has been reported in ClinVar as Likely pathogenic by one clinical laboratory (ClinVar Variation ID: 4056245) and is observed in COSMIC with 8 somatic occurrences (COSV52752618).
clinvar ↗No de novo observations, cosegregation data, proband phenotype scoring, or unaffected elderly carrier data were identified for this variant. PS2, PS4, PP1, PP4, BS2, and BS4 remain unassessed.
Applying the TP53 VCEP v2.4.0 Tavtigian point system: PS3 (+4) + PP3_Moderate (+2) + PM2_Supporting (+1) = +7 points, which falls in the Likely Pathogenic range (6-9 points).
cspec ↗
