LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-04
Case ID: NM_000546.6_c.818G_A_20261104_161737
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.6:c.818G>A

TP53  · NP_000537.3:p.(Arg273His)  · NM_000546.6
GRCh37: chr17:7577120 C>T  ·  GRCh38: chr17:7673802 C>T
Gene: TP53 Transcript: NM_000546.6
Final call
Likely Pathogenic
PS3 strong PM1 moderate PM2 supporting PP3 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.6
Protein
NP_000537.3:p.(Arg273His)
gnomAD AF
1.1152817139649381e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 strong reflects non-functional Kato results plus loss of function in three other eligible assays.
2
Likely Pathogenic: PM1 moderate applies because p.Arg273His affects TP53 codon 273, a VCEP-listed hotspot codon.
3
Likely Pathogenic: PM2 supporting applies because gnomAD v4.1 total allele frequency is 1.11528e-05.
4
Likely Pathogenic: PP3 supporting is pre-assigned by the VCEP exact-match row for c.818G>A with BayesDel C25.
5
Likely Pathogenic: PP5 supporting reflects the adjudicated ClinVar Expert Panel Pathogenic classification.
Final determination: Under the ClinGen TP53 VCEP Version 2.4 Tavtigian-style point framework, PS3 strong (4) plus PM1 moderate (2), PM2 supporting (1), PP3 supporting (1), and PP5 supporting (1) total 9 points, which 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 N/A Not applicable: c.818G>A is the missense variant p.Arg273His, whereas TP53 PVS1 is specified for null-variant paths such as nonsense or frameshift variants predicted to undergo NMD.
cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1 Not assessed Not assessed: no eligible alternate-nucleotide TP53 variant producing p.Arg273His was identified for comparison under the VCEP PS1 rule.
pm5_candidates
PS2 Not assessed Not assessed: the case strongly suggests de novo occurrence, but parental testing was not reported, so no VCEP PS2 point value can be assigned.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:15390294
PS3 Met Met at strong: the VCEP row for R273H records Kato non-functional results plus LOF in all three other available eligible assays and pre-assigns PS3.
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
PS4 Not assessed Not assessed: exact-variant LFS cases are reported, but complete VCEP point-assigning clinical details and case-control counts are unavailable.
cspec vcep_ps4_points_table PMID:15390294 PMID:16401470
PM1 Met Met at Moderate: p.Arg273His affects codon 273, one of the six TP53 hotspot codons explicitly listed by the VCEP.
cspec hotspots
PM2 Met Met at Supporting: gnomAD v4.1 total AF is 1.11528e-05, below the VCEP PM2 cutoff of 0.00003, with eligible ancestry frequencies below 0.00004.
cspec 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: the TP53 VCEP explicitly marks PM4 as not applicable, and c.818G>A is a missense substitution rather than a qualifying protein-length or in-frame consequence.
cspec
PM5 Not assessed Not assessed: no eligible different missense variant at TP53 residue 273 was documented with a VCEP-based pathogenicity determination.
pm5_candidates
PM6 N/A Not applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable.
cspec
PP1 Not assessed Not assessed: one father-carrier observation is reported, but affected-relative genotypes and the number of cosegregating meioses are unavailable.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:16401470
PP2 N/A Not applicable: the TP53 VCEP explicitly marks PP2 as not applicable.
cspec
PP3 Met Met at supporting: VCEP Supplementary Table S2 pre-assigns PP3 for c.818G>A with BayesDel class C25 and score 0.525881.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes spliceai
PP4 Not assessed Not assessed: the VCEP PP4 rule requires VAF 5-35% (or two observations at VAF 5-25%), but no VAF is reported.
cspec
PP5 Met Not applicable: the TP53 VCEP states that PP5 is not for use.
cspec clinvar
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 6.88e-06, below the VCEP BA1 threshold of 0.001, with the higher Ashkenazi Jewish group explicitly excluded.
cspec gnomad_v4
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 6.88e-06, below the VCEP BS1 lower threshold of 0.0003 after excluding Ashkenazi Jewish ancestry.
cspec gnomad_v4
BS2 Not assessed Not assessed: the available population data provide no count of unrelated cancer-free females aged at least 60 years from one source.
cspec
BS3 Not met Not met: the VCEP R273H row records Kato non-functional activity and LOF in three other eligible assays, contradicting both BS3 pathways.
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
BS4 Not assessed Not assessed: no tested affected family member is documented as lacking the variant, the VCEP requirement for BS4.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:15390294 PMID:16401470
BP1 N/A Not applicable: the TP53 VCEP excludes BP1 because truncating variants explain only part of TP53 disease causation.
cspec
BP2 N/A Not applicable: the TP53 VCEP Version 2.4 explicitly designates BP2 as Not Applicable.
cspec
BP3 N/A Not applicable: the TP53 VCEP explicitly marks BP3 as not applicable, and c.818G>A is a missense substitution rather than an in-frame deletion in a repetitive region.
cspec
BP4 Not met Not met: BayesDel 0.525881 exceeds the VCEP BP4 missense cutoff of <0.16, and SpliceAI provided no score.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes spliceai
BP5 N/A Not applicable: the TP53 VCEP explicitly marks BP5 as not applicable.
cspec
BP6 N/A Not applicable: the TP53 VCEP states that BP6 is not for use.
cspec
BP7 N/A Not applicable: c.818G>A is a missense variant, whereas VCEP BP7 applies only to synonymous or intronic variants.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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