Variant classification summary

NM_000546.6:c.797G>T

TP53 · NP_000537.3:p.(Gly266Val) · NM_000546.6

GRCh37: chr17:7577141 C>A · GRCh38: chr17:7673823 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gly266Val)

gnomAD AF

0.0 (v2.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Strong): p.(Gly266Val) is Non-functional on Kato et al. transactivation data with concordant loss of function across other eligible systematic assays.

2

PM2 (Supporting): absent from gnomAD v4.1 and gnomAD-Canada, with gnomAD v2.1 allele frequency 0 (0/248,882 alleles).

3

Classification: VUS — 5 points from PS3 Strong (+4) and PM2 Supporting (+1) fall within the VCEP's Uncertain Significance range (-1 to 5).

Final determination: Under the ClinGen TP53 VCEP v2.4 Tavtigian point-based combination rule, PS3 Strong (+4) plus PM2 Supporting (+1) sums to 5 points, which falls in the -1 to 5 range mapped to Uncertain Significance (Rule3).

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	Not applicable: this is a missense substitution, not a null variant (nonsense, frameshift, or canonical splice site), and SpliceAI max delta 0.17 is below the splice-impact threshold.	cspec spliceai
PS1	Not assessed	Not assessed: no alternate nucleotide change producing the same p.(Gly266Val) with an established VCEP pathogenic classification was available.	cspec
PS2	Not assessed	Not assessed: no de novo observation, parental testing results, or maternity/paternity confirmation was available.	cspec
PS3	Met	Met (Strong): p.(Gly266Val) is Non-functional on Kato et al. transactivation data, with concordant loss of function across the other eligible systematic assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet spliceai
PS4	Not assessed	Not assessed: no eligible germline proband observations with Li-Fraumeni-associated cancer were available for PS4 point assignment.	cspec vcep_ps4_points_table
PM1	Not assessed	Not assessed: codon 266 is not among the six VCEP hotspot codons (175, 245, 248, 249, 273, 282) required for PM1. Flagged for human review: cancerhotspots.org lists G266 in a significant hotspot, but no verified occurrence count was available.	cspec PMID:27328919
PM2	Met	Met (Supporting): absent from gnomAD v4.1 and gnomAD-Canada, with gnomAD v2.1 allele frequency 0 (0/248,882 alleles) below the 0.00003 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the TP53 VCEP v2.4 explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: this missense substitution produces no protein length change, and the VCEP marks PM4 as not applicable.	cspec
PM5	Not assessed	Not assessed: no different missense variant at codon 266 with an established pathogenic classification was available as a PM5 comparator.	cspec vcep_functional_worksheet
PM6	N/A	Not applicable: the TP53 VCEP v2.4 dropped PM6; de novo evidence is evaluated exclusively through PS2.	cspec
PP1	Not assessed	Not assessed: no family pedigree, carrier results, or countable meioses were available.	cspec
PP2	N/A	Not applicable: the TP53 VCEP v2.4 designates PP2 as not applicable.	cspec
PP3	Not assessed	Not assessed: BayesDel score 0.599 exceeds the 0.16 floor, but the required paired aGVGD class was unavailable.	cspec bayesdel spliceai vcep_pp3_bp4_codes
PP4	Not assessed	Not assessed: no eligible observations with variant allele fraction (VAF) data were available.	cspec
PP5	Not assessed	Not assessed: ClinVar holds no expert-panel pathogenic assertion for this variant, only a single-laboratory submission.	clinvar
BA1	Not met	Not met: allele frequency is 0 (0/248,882 gnomAD v2.1 alleles), below the FAF >=0.001 stand-alone benign threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no variant alleles observed in gnomAD, below the FAF >=0.0003 to <0.001 BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no carrier-level age, sex, cancer status, or variant allele fraction data were available.	cspec
BS3	Not met	Not met: functional data show loss of function (Kato Non-functional), the opposite of the BS3 'functional on Kato' requirement.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no affected relatives tested negative for the variant, so no non-segregation evidence was available.	cspec
BP1	N/A	Not applicable: the TP53 VCEP v2.4 designates BP1 as not applicable.	cspec
BP2	N/A	Not applicable: the TP53 VCEP v2.4 designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel; the VCEP marks BP3 as not applicable.	cspec
BP4	Not met	Not met: BayesDel score 0.599 is far above the <=-0.008 (Moderate) and <0.16 (Supporting) benign thresholds.	cspec bayesdel spliceai
BP5	N/A	Not applicable: the TP53 VCEP v2.4 designates BP5 as not applicable.	cspec
BP6	Not assessed	Not assessed: ClinVar holds no expert-panel benign or likely benign assertion for this variant.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous or intronic variant as BP7 requires.	cspec

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