Variant classification summary

NM_000546.6:c.760A>G

TP53 · NP_000537.3:p.(Ile254Val) · NM_000546.6

GRCh37: chr17:7577521 T>C · GRCh38: chr17:7674203 T>C

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

PM1 supporting PM2 supporting PP3 supporting BS3 strong BP6 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Ile254Val)

gnomAD AF

6.820859428287964e-06 (v4.1)

ClinVar

Likely Benign

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 supporting: p.Ile254Val has two somatic Cancer Hotspots occurrences.

2

PM2 supporting: gnomAD v4.1 total allele frequency is 6.82086e-06.

3

PP3 supporting: the VCEP assigns PP3 with Class C25 and BayesDel 0.17079.

4

BS3 strong: the VCEP worksheet records Functional Kato data and no LOF in most eligible assays.

5

BP6 supporting benign: an expert-panel ClinVar record classifies the variant as Likely benign.

Final determination: Under the TP53 VCEP Version 2.4 point-based framework, the applied criteria total -2 points, and scores from -6 through -2 classify a variant as Likely Benign.

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.760A>G causes the missense substitution p.(Ile254Val), not a TP53 null, nonsense, frameshift, splice-site, or copy-number variant.	cspec pvs1_variant_assessment vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: SpliceAI max delta was 0.003, but no eligible same-residue pathogenic or likely pathogenic comparator was confirmed and the comparator search ended with HTTP 429.	cspec pm5_candidates spliceai
PS2	Not assessed	Not assessed: no documented de novo proband observation, parental testing, or LFS cancer points are available to assign a PS2 strength.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Not met: the VCEP worksheet pre-assigns BS3 for I254V, with Functional Kato data and no LOF in Funk, Giacomelli, and Kotler assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	Not assessed: no proband phenotype or PS4 point total is available, and PS4-Points-Table.pdf has no c.760A>G, p.Ile254Val, or p.I254V entry.	cspec vcep_ps4_points_table
PM1	Met	Met at supporting: p.Ile254Val has 2 somatic occurrences for the same amino-acid change, within the VCEP's 2-9 Cancer Hotspots threshold.	cspec clinvar
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 6.82086e-06, below the TP53 VCEP PM2 threshold of 0.00003.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly designates PM3 as not applicable in Version 2.4.	cspec
PM4	N/A	Not applicable: the TP53 VCEP explicitly marks PM4 “Not Applicable,” and c.760A>G is a missense substitution without a protein-length change.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: SpliceAI max delta was 0.003, but zero same-residue comparators were retrieved and the comparator search recorded HTTP 429.	cspec pm5_candidates spliceai
PM6	N/A	Not applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no affected relatives, genotype segregation results, or countable 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.	cspec
PP3	Met	Met at supporting strength: VCEP Table S2 pre-assigns PP3 for c.760A>G, with Class C25 and BayesDel 0.17079 meeting the >=0.16 rule.	cspec vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: no qualifying VAF observation is available for PP4's 5-25% or 5-35% thresholds.	cspec
PP5	N/A	Not applicable: the TP53 VCEP explicitly prohibits use of PP5.	cspec
BA1	Not met	Not met: gnomAD v4.1 maximum group FAF is 5.01e-06, below the TP53 VCEP BA1 threshold of 0.001.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 maximum group FAF is 5.01e-06, below the TP53 VCEP BS1 lower threshold of 0.0003.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no single-source count of qualifying unrelated females aged at least 60 years without cancer is available.	cspec
BS3	Met	Met (strong): I254V is pre-assigned BS3 with Functional Kato data and no LOF in the majority of available eligible assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	Not assessed: no affected relatives with LFS-associated cancers and no family genotyping results are documented to establish non-segregation.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP states BP1 does not apply because truncating variants explain only part of disease causation.	cspec
BP2	N/A	Not applicable: the TP53 VCEP explicitly designates BP2 as not applicable in Version 2.4.	cspec
BP3	N/A	Not applicable: the TP53 VCEP explicitly marks BP3 “Not Applicable,” and c.760A>G is a missense substitution rather than an in-frame deletion.	cspec pvs1_variant_assessment
BP4	Not met	Not met: BayesDel 0.17079 exceeds the VCEP BP4 supporting cutoff of <0.16, despite SpliceAI maximum delta 0.003 being <0.2.	cspec vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: the TP53 VCEP explicitly marks BP5 as not applicable and provides no usable BP5 rule.	cspec
BP6	Met	Not applicable: the TP53 VCEP explicitly prohibits use of BP6.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants, whereas c.760A>G is a missense substitution producing p.Ile254Val.	cspec

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