Variant classification summary

NM_000546.6:c.742C>T

TP53 · NP_000537.3:p.(Arg248Trp) · NM_000546.6

GRCh37: chr17:7577539 G>A · GRCh38: chr17:7674221 G>A

Gene: TP53 Transcript: NM_000546.6

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 moderate PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg248Trp)

gnomAD AF

5.577528262575157e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: p.Arg248Trp is non-functional in Kato and loss of function in three other eligible assays.

2

PM1 moderate: the variant changes TP53 codon 248, an Expert Panel-designated hotspot codon.

3

PM2 supporting: gnomAD v4.1 allele frequency is 5.58e-06, below the TP53 threshold.

4

PP3 moderate: the VCEP table assigns C65 and BayesDel 0.533597 for p.Arg248Trp.

5

PP5 supporting: ClinGen TP53 Expert Panel classification is Pathogenic.

Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 point-based framework, a total of 10 evidence points maps to 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	N/A	Not applicable: c.742C>T is the missense p.Arg248Trp substitution, not one of the VCEP-specified null-variant classes for PVS1.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not met	Not met: no distinct nucleotide change producing the same pathogenic Arg248Trp amino-acid change was identified, despite SpliceAI maximum delta 0.004.	cspec spliceai clinvar
PS2	Not assessed	Not assessed: a ClinVar de novo label lacks documented parental testing and VCEP cancer-point data for PS2 scoring.	cspec
PS3	Met	Met, strong: the VCEP row for R248W reports non-functional Kato activity and LOF in all four other eligible assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
PS4	Not assessed	Not assessed: exact-variant family reports lack the individual Chompret, classic-LFS, or HER2-positive-breast-cancer details needed to assign the VCEP PS4 point total.	cspec vcep_ps4_points_table PMID:1978757 PMID:17606709
PM1	Met	Met at Moderate: p.Arg248Trp is a missense variant at codon 248, one of the TP53 VCEP’s explicitly approved PM1 codons.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 5.58e-06, below the TP53 VCEP PM2 threshold of 0.00003, with no multi-allele ancestry group exceeding 0.00004.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly designates PM3 as not applicable, regardless of available phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: p.Arg248Trp is a missense substitution, whereas the VCEP PM4 scope is protein-length change from in-frame indels or stop-loss variants.	cspec
PM5	Not assessed	Not assessed: zero usable pathogenic or likely pathogenic same-residue comparator variants were documented for codon 248 under the TP53 VCEP rule.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: one family has three affected and two unaffected carriers, but no count of phenotype-informative meioses is provided for the VCEP threshold.	cspec PMID:1978757 PMID:17606709
PP2	N/A	Not applicable: the TP53 VCEP explicitly marks PP2 as not applicable.	cspec
PP3	Met	Met at moderate strength: VCEP Table S2 pre-assigns PP3_moderate for p.Arg248Trp with BayesDel 0.533597 and a C65 classification.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP4	Not assessed	Not assessed: the VCEP PP4 rule requires a qualifying VAF, but no applicable VAF measurement is available for this germline variant.	cspec
PP5	Met	Not applicable: the TP53 VCEP explicitly marks PP5 as Not Applicable.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum group FAF is 2.47e-06, below the TP53 VCEP BA1 threshold of 0.001 and based on only one observed allele.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 maximum group FAF is 2.47e-06, below the TP53 VCEP BS1 range of 0.0003 to less than 0.001.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no single-source individual data document unrelated females aged at least 60 years without cancer, as required by the TP53 VCEP.	cspec gnomad_v4
BS3	Not met	Not met: R248W is non-functional in Kato and LOF in three other eligible assays, contrary to both VCEP BS3 paths.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
BS4	Not met	Not met: the variant was present in three affected family members, so lack of segregation in affected members was not demonstrated.	cspec PMID:1978757
BP1	N/A	Not applicable: the TP53 VCEP excludes BP1 because truncating variants cause only a portion of TP53-related disease.	cspec
BP2	N/A	Not applicable: the TP53 VCEP explicitly designates BP2 as not applicable, regardless of available phase or affected-proband observations.	cspec
BP3	N/A	Not applicable: p.Arg248Trp is a missense substitution, not an in-frame deletion or insertion in a repetitive region without known function.	cspec
BP4	N/A	Not applicable: the VCEP excludes BP4 for C65 variants, despite SpliceAI max delta 0.004 indicating no predicted splice impact.	cspec vcep_pp3_bp4_codes spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5	N/A	Not applicable: the TP53 VCEP explicitly marks BP5 as Not Applicable.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants, whereas c.742C>T is a missense substitution producing p.Arg248Trp.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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.