Variant classification summary

NM_000546.5:c.509C>T

TP53 · NP_000537.3:p.(Thr170Met) · NM_000546.5

GRCh37: chr17:7578421 G>A · GRCh38: chr17:7675103 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting BS3 supporting BP6 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Thr170Met)

gnomAD AF

1.548864186914452e-05 (v4.1)

ClinVar

Likely Benign

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.5:c.509C>T (p.Thr170Met) is a missense variant in exon 5 of TP53. This variant is present at very low frequency in gnomAD v4.1 (AF=1.55e-05, 25/1,614,086 alleles, 0 homozygotes), meeting PM2_Supporting per the TP53 VCEP specifications (total AF < 0.003%; no non-founder subpopulation with multiple alleles exceeds 0.004%).

2

Functional assay data from the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) demonstrates that p.Thr170Met is partially functional in the Kato et al. yeast transactivation assay and shows no loss of function across all available eligible assays (Funk, Giacomelli, Kotler), meeting BS3_Supporting per the VCEP functional rules.

3

In silico predictions were evaluated per the TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2), which assigns 'No evidence' for c.509C>T — neither PP3 nor BP4 is met. The variant has aGVGD Class C15 and BayesDel score 0.321305.

4

The variant has been reported in ClinVar with an expert panel classification of Likely Benign by the ClinGen TP53 Variant Curation Expert Panel (ClinVar ID: 184014). It has been observed in COSMIC as a somatic variant (n=14) but does not lie in a statistically significant cancer hotspot.

5

PVS1, PS1, PS2, PS4, PS5, PM1, PM5, PM6, PP1, PP2, PP4, PP5, BA1, BS1, BS2, BS4, BP1, BP2, BP4, BP5, BP6, and BP7 are either not met, not assessed due to lack of evidence, or not applicable per the TP53 VCEP specifications.

6

Tavtigian point total: PM2_Supporting (+1) + BS3_Supporting (−1) = 0 points, corresponding to a final classification of Uncertain Significance (VUS) per the TP53 VCEP v2.4.0 point-based system (VUS range: −1 to 5).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 0, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 applies to null variants (nonsense, frameshift, canonical splice sites, initiation codon, CNVs) per the TP53 VCEP PVS1 flowchart; NM_000546.5:c.509C>T is a missense variant (p.Thr170Met) and does not fall into any PVS1-eligible variant class.	cspec vcep_pvs1_flowchart
PS1	Not met	PS1 requires the same amino acid change (p.Thr170Met) to be previously established as Pathogenic or Likely Pathogenic per the TP53 VCEP specifications. The ClinGen TP53 VCEP has classified this exact variant (NM_000546.5:c.509C>T, p.Thr170Met) as Likely Benign, and no other nucleotide change encoding p.Thr170Met has been classified as P/LP by the VCEP.	cspec clinvar
PS2	Not assessed	No de novo occurrence data for NM_000546.5:c.509C>T was identified in the available evidence sources. None of the 24 filtered publications contained variant-specific de novo reports.
PS3	Not met	The TP53 VCEP Functional-worksheet.xlsx assigns BS3_Supporting (not PS3) to p.Thr170Met. Kato assay: Partially functional; no loss of function by Funk, Giacomelli, or Kotler assays. Functional evidence supports a benign effect, contradicting PS3.	vcep_functional_worksheet cspec
PS4	Not assessed	No case-control enrichment data or proband counts meeting the TP53 VCEP PS4 point-based thresholds (LFS-associated cancer scores) were available for this variant. The IARC TP53 database may contain case counts but they were not retrieved in variant-specific format usable for PS4 scoring.	cspec
PS5	Not met	PS5 requires a different nucleotide change at codon 170 leading to the same missense change (p.Thr170Met) that has been classified as Pathogenic. The only nucleotide change resulting in p.Thr170Met is c.509C>T, which is classified as Likely Benign by the ClinGen TP53 VCEP. No alternative nucleotide substitution at this codon has been established as P/LP per VCEP.	cspec clinvar
PM1	Not met	Thr170 is not among the VCEP-specified PM1 hot-spot codons (175, 245, 248, 249, 273, 282). The alternative PM1 rule via cancerhotspots.org requires ≥10 somatic occurrences for the same amino acid change (T170M); cancerhotspots.org does not list T170M as a significant hotspot (residue_significant=false, exact_variant_listed=no).	cspec
PM2	Met	This variant is present at very low frequency in gnomAD v4.1 (total AF = 1.55e-05, 25/1,614,086 alleles, 0 homozygotes). The highest non-founder subpopulation frequency is South Asian at 3.29e-05 (3 alleles). All non-excluded genetic ancestry groups with multiple alleles have AF < 0.00004, and total AF < 0.00003, meeting the TP53 VCEP PM2_Supporting threshold.	gnomad_v4 cspec
PM5	Not met	PM5 requires a different missense variant at the same amino acid residue (Thr170) previously classified as Pathogenic or Likely Pathogenic per the TP53 VCEP specifications. The pm5_candidates search returned no P/LP comparator variants at codon 170. All T170 substitutions in the VCEP functional worksheet are assigned BS3_Supporting or No evidence, none are P/LP.	vcep_functional_worksheet cspec
PM6	N/A	The ClinGen TP53 VCEP specifications designate PM6 as Not Applicable for TP53 variant interpretation.	cspec
PP1	Not assessed	No co-segregation data (variant tracking through affected family members across meioses) was identified for NM_000546.5:c.509C>T in any available source.
PP2	N/A	The ClinGen TP53 VCEP specifications designate PP2 as Not Applicable for TP53 variant interpretation.	cspec
PP3	Not met	The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns 'No evidence' to c.509C>T (p.Thr170Met). The variant is aGVGD Class C15 with BayesDel score 0.321305. Per the VCEP PP3/BP4 flowchart, Class C15 variants with BayesDel ≥0.16 would ordinarily receive PP3_Supporting, but the VCEP's pre-computed table has specifically overridden this to 'No evidence', indicating the VCEP does not consider in silico evidence sufficient for PP3 application at this residue.	vcep_pp3_bp4_codes cspec bayesdel
PP4	Not assessed	PP4 per the TP53 VCEP requires observations of the variant with variant allele fraction (VAF) 5-35% in blood. No VAF data was available for this variant in the evidence sources.	cspec
PP5	N/A	The ClinGen TP53 VCEP specifications designate PP5 as Not Applicable, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The TP53 VCEP BA1 threshold requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in a continental subpopulation. gnomAD v4.1 grpmax FAF = 8.78e-06, far below this threshold. The variant is too rare in population databases to meet BA1.	gnomad_v4 cspec
BS1	Not met	The TP53 VCEP BS1 threshold requires a filtering allele frequency (FAF) ≥0.0003 (0.03%) but <0.001 in a continental subpopulation. gnomAD v4.1 grpmax FAF = 8.78e-06, which is below the BS1 threshold. Even the highest raw subpopulation AF (South Asian, 3.29e-05) is below 0.0003.	gnomad_v4 cspec
BS2	Not assessed	BS2 requires observation of the variant in unrelated females who have reached at least 60 years of age without cancer. No such data was available in the evidence sources for this variant.	cspec
BS3	Met	The TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns BS3_Supporting to p.Thr170Met. The variant is Partially functional in the Kato et al. (PMID:12826609) assay and demonstrates no loss of function (noLOF) across all available eligible assays (Funk, Giacomelli, Kotler). This satisfies the VCEP BS3_Supporting rule: Partially functional on Kato data AND no evidence of LOF by all available assays.	vcep_functional_worksheet cspec
BS4	Not assessed	BS4 requires observation of lack of segregation in affected family members (family members with LFS-associated cancers lacking the variant). No segregation data of any kind was identified for this variant.	cspec
BP1	N/A	The ClinGen TP53 VCEP specifications designate BP1 as Not Applicable for TP53 variant interpretation.	cspec
BP2	N/A	The ClinGen TP53 VCEP specifications designate BP2 as Not Applicable for TP53 variant interpretation.	cspec
BP4	Not met	The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns 'No evidence' to c.509C>T (p.Thr170Met). Although the BayesDel score (0.321305) is elevated, the aGVGD class is C15 (not C65), and the VCEP's pre-computed table specifically assigns 'No evidence' rather than BP4, indicating the VCEP does not consider the in silico evidence sufficient for either PP3 or BP4 at this residue.	vcep_pp3_bp4_codes cspec bayesdel
BP5	N/A	The ClinGen TP53 VCEP specifications designate BP5 as Not Applicable for TP53 variant interpretation.	cspec
BP6	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants. NM_000546.5:c.509C>T is a missense variant (p.Thr170Met) and does not fall under BP7 per the TP53 VCEP rules.	cspec

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