NM_000546.5:c.509C>T (p.Thr170Met) is a missense variant in exon 5 of TP53. The variant has been classified as Likely Benign by the ClinGen TP53 Variant Curation Expert Panel (ClinVar variation ID 184014, reviewed by expert panel).

Population data from gnomAD v4.1 shows the variant is present at very low frequency (AF=1.55e-05, 25/1,614,086 alleles; grpmax FAF=8.78e-06), meeting PM2_Supporting (total AF < 0.00003; no subpopulation with multiple alleles exceeds 0.00004). The variant does not meet BA1 or BS1 thresholds.

In silico predictions using BayesDel (score 0.321) and REVEL (score 0.868) suggest a potentially deleterious effect, but BP4 is not met as the BayesDel score exceeds the benign thresholds. The VCEP PP3/BP4 pre-computed assignment is not available for this variant. SpliceAI scores are unavailable.

The variant lies at codon 170, which is not among the VCEP-specified PM1 hotspot codons (175, 245, 248, 249, 273, 282), and is not in a statistically significant cancer hotspot. PM1 is not met.

Functional evidence (PS3/BS3) could not be assessed because the variant is absent from the VCEP Functional-worksheet (Supplementary Table S3). OncoKB suggests Likely Loss-of-function, but primary assay data from Kato et al. and Giacomelli et al. could not be verified from available sources.

Clinical evidence for PS2 (de novo), PS4 (case enrichment), PP1 (co-segregation), PP4 (VAF observations), BS2 (cancer-free older females), and BS4 (lack of segregation) remains unassessed due to insufficient data in the evidence packet.

Based on verifiable evidence, PM2_Supporting is the only criterion met. Under the TP53 VCEP Tavtigian point system (version 2.4.0), a single supporting pathogenic criterion (+1 point) with no assessed benign criteria would place this variant in the VUS range (Tavtigian points -1 to +5). However, the ClinGen TP53 VCEP has classified this variant as Likely Benign, indicating that additional benign evidence (likely BS3 functional data and/or BS2 population data) exists that is not verifiable from the current evidence packet.