Variant classification summary

NM_000546.6:c.877G>A

TP53 · NP_000537.3:p.(Gly293Arg) · NM_000546.6

GRCh37: chr17:7577061 C>T · GRCh38: chr17:7673743 C>T

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

PM2 supporting BS3 strong BP4 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gly293Arg)

gnomAD AF

1.8585403024464585e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: qualifying gnomAD allele frequency is below 0.00003 with no homozygotes.

2

BS3 strong: the TP53 worksheet records functional Kato data and no loss of function in Funk and Giacomelli assays.

3

BP4 moderate: the exact TP53 lookup assigns BP4_moderate with BayesDel -0.0095438 and Class C0.

Final determination: Under the TP53 Version 2.4 point-based framework, PM2 supporting contributes +1, BS3 strong contributes -4, and BP4 moderate contributes -2; the total of -5 falls in the Likely Benign range of -6 through -2.

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.877G>A is a missense variant producing p.Gly293Arg, outside the TP53 VCEP PVS1 null-variant and splice-site rules.	pvs1_gene_context vcep_pvs1_flowchart
PS1	Not assessed	Not assessed: no qualifying pathogenic or likely pathogenic variant producing the same amino-acid change as p.Gly293Arg is documented in the reviewed evidence.	vcep_output clinvar
PS2	Not assessed	Not assessed: no proband cancer, de novo observation, or parental testing is documented, so the VCEP PS2 point thresholds cannot be applied.	vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application final_classification_framework
PS3	Not met	Not met: TP53 VCEP assigns BS3 because Kato is functional and Funk/Giacomelli are noLOF, with no majority-LOF pattern required for PS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609
PS4	Not assessed	Not assessed: no proband phenotype or PS4 point total is available, and the searched PS4-Points-Table.pdf has no c.877G>A, p.Gly293Arg, or p.G293R entry.	vcep_ps4_points_table PMID:1686725 PMID:21343334 PMID:23894400
PM1	Not met	Not met: p.Gly293Arg is at codon 293, outside the six TP53 PM1 codons, and cancerhotspots returned no significant hotspot for TP53 G293.	vcep_output final_classification_framework vcep_hotspots_vision_instruction
PM2	Met	Met at supporting: gnomAD v2.1 non-cancer exome AF was 8.44067e-06, below the TP53 PM2 threshold of 0.00003, with no homozygotes.	final_classification_framework gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the TP53 Expert Panel Version 2.4 framework explicitly designates PM3 as Not Applicable.	final_classification_framework
PM4	N/A	Not applicable: the single-nucleotide missense substitution p.Gly293Arg does not alter protein length through an in-frame indel or stop-loss event.	final_classification_framework
PM5	Not assessed	Not assessed: p.Gly293Trp is reported at residue 293, but its pathogenicity is unestablished and the same-residue search ended with an HTTP 429 error.	vcep_output pm5_candidates PMID:1686725
PM6	N/A	Not applicable: the governing TP53 framework explicitly designates PM6 as Not Applicable.	final_classification_framework
PP1	Not assessed	Not assessed: no relatives, meioses, or cosegregation data are documented, so the VCEP PP1 thresholds cannot be applied.	vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application final_classification_framework
PP2	N/A	Not applicable: the governing TP53 VCEP explicitly marks PP2 as Not Applicable.	vcep_output
PP3	Not met	Not met: the exact TP53 lookup entry reports BayesDel -0.0095438, below the VCEP PP3 missense threshold of 0.16, and assigns BP4_moderate instead.	vcep_pp3_bp4_codes
PP4	Not assessed	Not assessed: no PP4-qualifying VAF observation is available; the framework requires VAF 5-35% for Supporting or at least two 5-25% observations for Moderate.
PP5	Not met	Not met: exact-match ClinVar variation 230208 has zero Expert Panel submissions and no Expert Panel Pathogenic or Likely Pathogenic classification.	clinvar
BA1	Not met	Not met: highest qualifying population frequency was 3.2759e-05, below the TP53 VCEP BA1 FAF threshold of 0.001, with only one observed allele.	final_classification_framework gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum observed ancestry frequency was 3.2759e-05, below the TP53 VCEP BS1 FAF threshold of 0.0003 and based on one allele.	final_classification_framework gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no single-source records identify at least two unrelated cancer-free females aged 60 years or older carrying this variant.	final_classification_framework gnomad_v2 gnomad_v4
BS3	Met	Met, strong: TP53 VCEP assigns BS3 because Kato is functional and both available additional assays, Funk and Giacomelli, are noLOF.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609
BS4	Not assessed	Not assessed: no affected-relative genotypes or documented non-segregation are available for this variant.	final_classification_framework vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:1686725 PMID:21343334 PMID:23894400
BP1	N/A	Not applicable: the governing TP53 VCEP explicitly marks BP1 as Not Applicable.	vcep_output
BP2	N/A	Not applicable: the TP53 Expert Panel Version 2.4 framework explicitly designates BP2 as Not Applicable.	final_classification_framework
BP3	N/A	Not applicable: p.Gly293Arg is a missense substitution, not an in-frame insertion or deletion in a repetitive region.	final_classification_framework
BP4	Met	Met at moderate strength: the exact TP53 lookup assigns BP4_moderate with BayesDel -0.0095438 and class C0.	vcep_pp3_bp4_codes
BP5	N/A	Not applicable: the governing TP53 framework explicitly marks BP5 as Not Applicable.
BP6	Not met	Not met: ClinVar exact-match variation 230208 has no Expert Panel submission, so its single-submitter Likely benign assertion cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: c.877G>A is a missense variant producing p.Gly293Arg, whereas BP7 applies only to synonymous or qualifying intronic variants.

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.