Variant classification summary

NM_000546.5:c.782G>C

TP53 · NP_000537.3:p.(Ser261Thr) · NM_000546.5

GRCh37: chr17:7577499 C>G · GRCh38: chr17:7674181 C>G

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

PM2 supporting BS3 strong BP4 moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Ser261Thr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: c.782G>C is absent from the reported gnomAD datasets.

2

BS3 Strong: TP53 functional assays show Functional Kato results and a majority of non-Kato assays without loss of function.

3

BP4 Moderate: the TP53 VCEP pre-assigns BP4_moderate for p.Ser261Thr with BayesDel score -0.162486.

Final determination: Under the TP53 VCEP Version 2.4 point-based rule, a net score of -5, calculated from PM2 Supporting (+1), BS3 Strong (-4), and BP4 Moderate (-2), falls in the -6 to -2 Likely Benign interval.

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: c.782G>C is an exon 7 missense variant producing p.Ser261Thr, not a VCEP-defined null or canonical splice variant for PVS1.	cspec spliceai vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not met	Not met: no qualifying pathogenic p.Ser261Thr comparator is documented, and SpliceAI max delta 0.638 exceeds the VCEP <0.2 no-splicing requirement.	cspec spliceai
PS2	Not assessed	Not assessed: no qualifying de novo proband, parental confirmation, or PS2 point total is available for NM_000546.5:c.782G>C.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Not met: Kato classified p.S261T as Functional, while the available non-Kato assays were mostly noLOF (2 noLOF versus 1 LOF).	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec
PS4	Not assessed	Not assessed: no proband phenotype or cancer-history data are available to assign TP53 PS4 points against the 1-1.5, 2-3.5, 4-7.5, or >=8 thresholds.	cspec clinvar vcep_ps4_points_table
PM1	Not met	Not met: residue 261 is outside the VCEP hotspot codons, cancerhotspots returned no result, and vcep_materials domain_tables is empty.	cspec
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, with observed allele frequency 0 versus the TP53 VCEP threshold below 0.00003.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP version 2.4 explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.Ser261Thr is a single-amino-acid substitution with no protein-length change, whereas PM4 concerns qualifying length-altering variants.	cspec
PM5	Not met	Not met: the residue-261 review found 0 qualifying pathogenic or likely pathogenic alternate missense comparators for PM5.	cspec pm5_candidates vcep_functional_worksheet vcep_pp3_bp4_codes
PM6	N/A	Not applicable: the TP53 VCEP dropped PM6 and directs all de novo evidence to PS2.	cspec
PP1	Not assessed	Not assessed: no variant-positive affected relatives, obligate carriers, or countable PP1 meioses are documented for this variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP explicitly designates PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: missense REVEL 0.504 is below the 0.644 PP3 supporting threshold, and the VCEP row assigns BP4_moderate rather than PP3.	cspec vcep_pp3_bp4_codes revel
PP4	Not assessed	Not assessed: no multigene-panel VAF observation is available to compare with the TP53 PP4 Supporting 5-35% or Moderate 5-25% ranges.	cspec
PP5	N/A	Not applicable: the TP53 VCEP prohibits PP5, and ClinVar has zero exact-variant expert-panel submissions supporting Pathogenic or Likely pathogenic.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below the TP53 VCEP BA1 FAF threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below the TP53 VCEP BS1 FAF range beginning at 0.0003.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying unaffected females aged 60 years or older carrying the variant were reported for the TP53 VCEP BS2 threshold of at least 2.	cspec gnomad_v2 gnomad_v4
BS3	Met	Met, strong: the VCEP row assigns BS3 with Kato Functional and majority noLOF among non-Kato assays (2 of 3), subject to splice-effect review.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec spliceai
BS4	Not assessed	Not assessed: no affected non-carrier relatives or other documented lack-of-segregation evidence is available.	cspec
BP1	N/A	Not applicable: the TP53 VCEP explicitly excludes BP1 because truncating variants are not the primary disease mechanism.	cspec
BP2	N/A	Not applicable: the TP53 VCEP version 2.4 explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: p.Ser261Thr is a missense substitution, not an in-frame insertion or deletion in a repetitive region lacking known function.	cspec
BP4	Met	Met at moderate: the TP53 VCEP table pre-assigns BP4_moderate for c.782G>C with BayesDel -0.162486.	cspec vcep_pp3_bp4_codes revel
BP5	N/A	Not applicable: the TP53 VCEP marks BP5 as not applicable, regardless of the available uncertain-significance ClinVar record.	cspec clinvar
BP6	N/A	Not applicable: the TP53 VCEP prohibits BP6, and ClinVar has zero exact-variant expert-panel submissions supporting Benign or Likely benign.	cspec clinvar
BP7	N/A	Not applicable: c.782G>C is missense p.Ser261Thr, not a synonymous variant required for BP7.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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