Variant classification summary

NM_000546.6:c.840A>C

TP53 · NP_000537.3:p.(Arg280Ser) · NM_000546.6

GRCh37: chr17:7577098 T>G · GRCh38: chr17:7673780 T>G

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg280Ser)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Strong): functional assays demonstrate loss of function - non-functional on Kato data and loss of function in most other eligible assays.

2

PM2 (Supporting): the variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0.

3

PP3 (Moderate): VCEP pre-computed assignment records Align-GVGD Class C65 and BayesDel 0.47, supporting a pathogenic effect.

4

Likely Pathogenic: 7 points under the TP53 VCEP v2.4 framework (PS3 strong +4, PM2 supporting +1, PP3 moderate +2).

Final determination: Under the TP53 VCEP Version 2.4 Tavtigian-style point ranges, a total pathogenic-evidence score from 6 through 9 is classified as Likely Pathogenic; the applied criteria total 7 points.

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: a missense substitution with no predicted splice impact (max SpliceAI delta 0.004), so no loss-of-function null mechanism applies.	cspec vcep_pvs1_flowchart spliceai
PS1	Not assessed	Not assessed: the only available ClinVar submissions are non-expert-panel, so no qualifying pathogenic same-amino-acid comparator exists.	cspec clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband parental-testing, mosaicism, or family-history data were available to establish a de novo origin.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	Met (Strong): functional assays show loss of function - non-functional on Kato data and loss of function in most other eligible assays.	cspec vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	Not assessed: no case-control prevalence or verified Li-Fraumeni proband data were available for point scoring.	cspec vcep_ps4_points_table vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PM1	Not assessed	Not assessed: codon 280 falls outside the VCEP hotspot codons (175, 245, 248, 249, 273, 282), and no Arg280Ser occurrence count was available.	cspec vcep_hotspots_vision_instruction vcep_output PMID:27328919 PMID:10761706 PMID:29979965 PMID:12826609 PMID:30224644
PM2	Met	Met (Supporting): absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0, below the 0.00003 allele-frequency threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: the TP53 VCEP specification excludes PM3 for TP53/Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: PM4 is excluded by the TP53 VCEP, and Arg280Ser is a single-residue substitution with no protein-length change.	cspec
PM5	Not assessed	Not assessed: insufficient evidence was available - no qualifying same-residue pathogenic comparator variant could be confirmed.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no documentation that the variant is assumed de novo, or the proband phenotype needed to score it, was available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP1	Not assessed	Not assessed: no family carrier-testing, affected-relative, or meiosis data were available for cosegregation scoring.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: PP2 is excluded by the TP53 VCEP specification.	cspec
PP3	Met	Met (Moderate): VCEP pre-computed assignment for Arg280Ser - Align-GVGD Class C65 and BayesDel 0.47 - supports a pathogenic effect.	cspec vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: no blood or tumor variant-allele-fraction or independent observation-count data were available.	cspec
PP5	N/A	Not applicable: the TP53 VCEP excludes PP5, and the ClinVar record has zero expert-panel submissions.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, so no population frequency reached the 0.001 BA1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, so no frequency fell in the required 0.0003-0.001 range.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no cohort data on unrelated female carriers who reached age 60 without cancer were available.	cspec
BS3	Not met	Not met: functional assays show loss of function, failing the benign functional pathway BS3 requires.	cspec vcep_functional_worksheet spliceai PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	Not assessed: no affected-relative variant results or phenotype data were available to test lack of segregation.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: BP1 is excluded by the TP53 VCEP specification.	cspec
BP2	N/A	Not applicable: BP2 is excluded by the TP53 VCEP, and no phase observations with other pathogenic TP53 variants were documented.	cspec
BP3	N/A	Not applicable: Arg280Ser is a missense substitution, not an in-frame insertion/deletion in a repeat region.	cspec
BP4	Not met	Not met: the VCEP worksheet assigns pathogenic-direction PP3_moderate to this variant, not benign-direction BP4.	cspec vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: BP5 is excluded by the TP53 VCEP specification.	cspec
BP6	N/A	Not applicable: the TP53 VCEP excludes BP6, and no benign expert-panel ClinVar assertion exists.	cspec clinvar
BP7	N/A	Not applicable: Arg280Ser is a missense variant, not synonymous or intronic as BP7 requires.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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