NM_000546.6:c.370T>C (p.Cys124Arg) is a missense variant in TP53 exon 4.
Functional studies demonstrate that p.Cys124Arg is non-functional in the Kato transcriptional assay and shows loss of function in both the Giacomelli and Kotler assays, meeting the TP53 VCEP criteria for PS3 (Strong).
In silico prediction tools support a deleterious effect: aGVGD Class C65, BayesDel score 0.25469, and REVEL score 0.883. The TP53 VCEP PP3-BP4-codes.xlsx assigns PP3_moderate.
SpliceAI predicts no significant splicing impact (max delta score 0.02), consistent with a missense effect rather than a splicing alteration.
spliceai ↗This variant has been reported in ClinVar as Likely pathogenic by a single clinical laboratory (SCV006277400).
clinvar ↗The variant has been observed in somatic cancers (COSMIC COSV52752618, n=8).
Applying the TP53 VCEP v2.4.0 Tavtigian point-based framework: PS3 (Strong) = +4, PM2_Supporting = +1, PP3_moderate = +2. Total points = +7 (range 6-9), consistent with Likely Pathogenic.
cspec ↗No benign criteria are met. No evidence for BA1, BS1, BS2, BS3, BS4, or BP4 was identified.
