Variant classification summary

NM_000546.6:c.820G>T

TP53 · NP_000537.3:p.(Val274Phe) · NM_000546.6

GRCh37: chr17:7577118 C>A · GRCh38: chr17:7673800 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Val274Phe)

gnomAD AF

6.195418364211298e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Strong): non-functional in the Kato assay and loss-of-function in the Funk, Giacomelli, and Kotler assays per the TP53 VCEP functional worksheet.

2

PM2 (Supporting): essentially absent from population databases, with gnomAD v4.1 total allele frequency 6.2e-07, below the 0.00003 threshold.

3

PP3 (Supporting): the VCEP per-variant table assigns PP3 on Align-GVGD class C45 and BayesDel 0.315825.

4

Overall: Likely Pathogenic, from PS3 strong (+4) + PM2 supporting (+1) + PP3 supporting (+1) = 6 points in the TP53 VCEP v2.4 framework.

Final determination: Under the TP53 VCEP v2.4 point-based framework, a total of 6 points maps to Likely Pathogenic.

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	Not met	Not met: missense change with no premature stop, frameshift, or splice effect (SpliceAI max delta 0.00).	cspec spliceai
PS1	Not assessed	Not assessed: no previously established pathogenic or likely pathogenic variant producing the same p.Val274Phe change is available.	cspec pm5_candidates spliceai
PS2	Not assessed	Not assessed: no confirmed de novo observation with parental testing and maternity/paternity confirmation was available.	cspec PMID:31775759
PS3	Met	Met (Strong): non-functional in the Kato assay and loss-of-function in the Funk, Giacomelli, and Kotler assays per the VCEP worksheet.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4	Not assessed	Not assessed: no qualifying germline proband observations; the only variant report is tumor-only.	cspec
PM1	Not assessed	Not assessed: residue 274 is outside the VCEP PM1 codon list (175, 245, 248, 249, 273, 282).	cspec
PM2	Met	Met (Supporting): gnomAD v4.1 total allele frequency 6.2e-07 (1/1,614,096 alleles), below the 0.00003 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: PM3 does not apply to TP53, which the VCEP treats as an autosomal dominant disorder.	cspec
PM4	N/A	Not applicable: missense substitution with no protein-length change.	cspec
PM5	Not assessed	Not assessed: no different pathogenic or likely pathogenic missense variant at residue 274 is available as a comparator.	cspec pm5_candidates spliceai
PM6	N/A	Not applicable: PM6 is dropped under the TP53 VCEP; de novo evidence is scored exclusively by PS2.	cspec
PP1	Not assessed	Not assessed: no affected relatives or countable meioses in families with LFS-associated cancers were available.	cspec PMID:31775759
PP2	N/A	Not applicable: PP2 is not permitted for TP53 under the VCEP specifications.	cspec
PP3	Met	Met (Supporting): the VCEP per-variant table assigns PP3 based on Align-GVGD class C45 and BayesDel 0.315825.	cspec vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: no multigene-panel tumor VAF observations (supporting requires 5-35%) were available.	cspec
PP5	Not met	Not met: no exact-variant ClinVar expert-panel Pathogenic or Likely Pathogenic assertion is present.	clinvar
BA1	Not met	Not met: highest ancestry allele frequency 8.5e-07 versus the >=0.001 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: highest ancestry allele frequency 8.5e-07 versus the >=0.0003 BS1 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying carrier observations (unrelated females aged 60+ without cancer) were available.	cspec gnomad_v4
BS3	Not met	Not met: the VCEP worksheet records loss-of-function results for V274F, not the functional pattern BS3 requires.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no family genotypes or segregation data were available to evaluate lack of segregation.	cspec PMID:31775759
BP1	N/A	Not applicable: p.Val274Phe is a missense variant, and BP1 applies only to truncating variants.	cspec
BP2	N/A	Not applicable: BP2 is not an applicable TP53 VCEP criterion.	cspec
BP3	N/A	Not applicable: missense substitution, not an in-frame insertion or deletion.	cspec
BP4	Not met	Not met: the VCEP assigns pathogenic-direction PP3, not BP4, to this missense variant.	cspec vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: BP5 is not applicable under the TP53 VCEP v2.4 specifications.	cspec
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely Benign assertion is present.	clinvar
BP7	N/A	Not applicable: missense variant, not synonymous or intronic.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.