Variant classification summary

NM_000546.6:c.1066G>C

TP53 · NP_000537.3:p.(Gly356Arg) · NM_000546.6

GRCh37: chr17:7573961 C>G · GRCh38: chr17:7670643 C>G

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

PM2 supporting BS3 strong BP4 moderate BP6 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gly356Arg)

gnomAD AF

4.337163668447382e-06 (v4.1)

ClinVar

Likely Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): essentially absent from population databases - gnomAD v4.1 allele frequency 4.34e-06, below the 0.00003 threshold.

2

BS3 (Strong): VCEP functional data show normal protein function (Kato 'Functional', no loss of function).

3

BP4 (Moderate): BayesDel -0.347 and SpliceAI max delta 0.004 indicate no pathogenic computational or splicing evidence.

4

BP6 (Supporting): ClinGen TP53 Expert Panel classified this variant Likely Benign.

5

Final classification: Likely Benign, per TP53 VCEP Rule 4 (combined score -6, within the -6 to -2 range).

Final determination: TP53 VCEP v2.4 point total -6 falls in Rule4 (>= -6 and <= -2) => 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: this is a missense substitution, not a null variant, so the loss-of-function rule does not apply.	cspec vcep_pvs1_flowchart pvs1_generic_framework
PS1	Not assessed	Not assessed: insufficient evidence was available to identify an alternate nucleotide change at this residue with an established pathogenic classification.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no proband-level phenotype data or confirmed parental genotypes were available to establish de novo status.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Not met: VCEP functional data show normal protein activity (Kato 'Functional', no loss of function), directly contradicting the loss-of-function requirement.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec
PS4	Not assessed	Not assessed: no verified case series or Li-Fraumeni cancer-point data were available for this variant.	cspec vcep_ps4_points_table vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PM1	Not met	Not met: codon 356 is not among the six VCEP hotspot codons, and cancerhotspots.org shows no hotspot match.	cspec oncokb
PM2	Met	Met (Supporting): gnomAD v4.1 allele frequency 4.34e-06 (7/1,613,958 alleles) is below the 0.00003 threshold.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP specification marks PM3 as not applicable for this gene.	cspec
PM4	N/A	Not applicable: missense substitution causes no protein length change, and the VCEP marks PM4 not applicable.	cspec
PM5	Not assessed	Not assessed: no prior VCEP-classified pathogenic missense variant at residue 356 was documented; insufficient evidence was available.	cspec pm5_candidates vcep_functional_worksheet
PM6	N/A	Not applicable: the TP53 VCEP uses PS2 exclusively for de novo evidence, dropping PM6.	cspec
PP1	Not assessed	Not assessed: no family segregation data (affected relatives or meiosis counts) were available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP specification marks PP2 as not applicable.	cspec
PP3	Not met	Not met: BayesDel score -0.347 is far below the 0.16 pathogenic threshold, and SpliceAI max delta is 0.004.	cspec bayesdel spliceai
PP4	Not assessed	Not assessed: no phenotype-specificity evidence or qualifying VAF observations were available.	cspec
PP5	Not met	Not met: the ClinVar record's ClinGen TP53 Expert Panel classification is Likely Benign, not Pathogenic or Likely Pathogenic.	clinvar
BA1	Not met	Not met: highest gnomAD v4.1 ancestry frequency is 5.93e-06, far below the 0.001 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: highest gnomAD v4.1 ancestry frequency is 5.93e-06, below the 0.0003 BS1 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no cohort data documenting two or more cancer-free women aged 60 or older were available.	cspec
BS3	Met	Met (Strong): VCEP functional worksheet assigns BS3, with Kato 'Functional' and no loss of function across eligible assays.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec
BS4	Not assessed	Not assessed: no affected-family-member genotype data were available to establish absence of segregation.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP specification marks BP1 as not applicable.	cspec
BP2	N/A	Not applicable: the TP53 VCEP specification marks BP2 as not applicable.	cspec
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel, and the VCEP marks BP3 not applicable.	cspec
BP4	Met	Met (Moderate): BayesDel -0.347 is below the -0.008 cutoff and SpliceAI max delta 0.004 shows no splicing impact. Flagged for human review: aGVGD class not confirmed to exclude C65, which would void BP4.	cspec bayesdel spliceai
BP5	N/A	Not applicable: the TP53 VCEP specification marks BP5 as not applicable.	cspec
BP6	Met	Met (Supporting): ClinGen TP53 Variant Curation Expert Panel classified this variant Likely Benign.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; this is a missense substitution.	cspec

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