LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-25
Case ID: NM_000546.5_c.1066G_C_20260525_033324
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.1066G>C

TP53  · NP_000537.3:p.(Gly356Arg)  · NM_000546.5
GRCh37: chr17:7573961 C>G  ·  GRCh38: chr17:7670643 C>G
Gene: TP53 Transcript: NM_000546.5
Final call
PM2_Supporting BS3_Strong BP4_Moderate BP6_Supporting_Benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.5
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
The TP53 c.1066G>C (p.Gly356Arg) variant has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classified it as Likely Benign.
2
This variant is rare in population databases, with gnomAD v4.1 total allele frequency 4.34e-06, grpmax filtering allele frequency 2.47e-06, gnomAD v2.1 total allele frequency 3.99e-06, and no observation in gnomAD-Canada, which supports PM2 at a supporting level but is well below BA1 and BS1 thresholds.
3
In the TP53 VCEP functional worksheet, p.Gly356Arg is classified as Functional in Kato-class data and noLOF in Giacomelli-class data, supporting BS3 and arguing against PS3.
4
TP53-specific computational assessment supports a benign interpretation: the TP53 VCEP bioinformatic worksheet assigns BP4_moderate, BayesDel is -0.347259, SpliceAI predicts no splice effect with max delta score 0.00, and REVEL is 0.138.
Final determination: Under the TP53 ClinGen VCEP point-based framework, a total of -6 points supports a Likely benign classification.
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 This missense variant does not fall within the TP53 null-variant or canonical splice categories used for PVS1, and SpliceAI predicts no splice effect (max delta score 0.00).
pvs1_gene_context pvs1_variant_assessment spliceai cspec
PS1 Not met An alternative nucleotide change producing the same amino acid substitution at codon 356 is present in ClinVar, but it does not provide a prior TP53 VCEP pathogenic or likely pathogenic assertion that would support PS1.
clinvar cspec
PS2 Not assessed No confirmed de novo observation with sufficient parental testing and phenotype scoring was identified for this variant.
clinvar cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3 Not met Available TP53 functional evidence does not support a damaging effect. In the TP53 VCEP functional worksheet, p.Gly356Arg is listed as functional in Kato-class data and as no loss of function in Giacomelli-class data, which argues against PS3.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 cspec
PS4 Not assessed No phenotype-weighted Li-Fraumeni syndrome proband data were identified to support PS4, although this criterion remains potentially assessable only after PM2 is met.
cspec vcep_ps4_points_table gnomad_v4
PM1 Not met This codon is not one of the TP53 codons explicitly specified for PM1, and no Cancer Hotspots hotspot row was identified for p.Gly356Arg.
cspec hotspots
PM2 Met This variant is rare in population databases. In gnomAD v4.1, the total allele frequency is 4.34e-06 and the grpmax filtering allele frequency is 2.47e-06, both below the TP53 VCEP PM2 threshold of 3.0e-05; it is also absent from gnomAD-Canada.
gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3 N/A PM3 is not used for TP53 in this framework.
cspec
PM4 N/A PM4 is not used for TP53 in this framework.
cspec
PM5 Not met Other missense changes at codon 356 identified in ClinVar do not provide qualifying TP53 VCEP pathogenic or likely pathogenic same-residue comparator evidence for PM5.
clinvar pm5_candidates cspec
PM6 N/A PM6 is not used for TP53 in this framework.
cspec
PP1 Not assessed No informative cosegregation data were identified for this variant.
clinvar cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2 N/A PP2 is not used for TP53 in this framework.
cspec
PP3 Not met Available computational evidence does not support a damaging effect. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.1066G>C; BayesDel is -0.347259, SpliceAI max delta score is 0.00, and REVEL is 0.138.
vcep_pp3_bp4_codes bayesdel spliceai revel cspec
PP4 Not assessed No low-variant-allele-fraction constitutional mosaicism evidence or other TP53-specific PP4 clinical context was identified for this variant.
cspec
PP5 N/A PP5 is not used for TP53 in this framework.
cspec
BA1 Not met Population data do not reach the TP53 VCEP BA1 threshold. The gnomAD v4.1 grpmax filtering allele frequency is 2.47e-06, which is below the BA1 threshold of 0.001.
gnomad_v4 cspec
BS1 Not met Population data do not reach the TP53 VCEP BS1 threshold. The gnomAD v4.1 grpmax filtering allele frequency is 2.47e-06, which is below the BS1 threshold of 0.0003.
gnomad_v4 cspec
BS2 Not assessed No single-source dataset of unaffected older female carriers was identified for this variant.
cspec
BS3 Met Published TP53 functional evidence supports retained protein function. In the TP53 VCEP functional worksheet, p.Gly356Arg is classified as Functional in Kato-class data and noLOF in Giacomelli-class data, with a preliminary functional code of BS3.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 cspec
BS4 Not assessed No informative lack-of-segregation data were identified for this variant.
clinvar cspec
BP1 N/A BP1 is not used for TP53 in this framework.
cspec
BP2 N/A BP2 is not used for TP53 in this framework.
cspec
BP3 N/A BP3 is not used for TP53 in this framework.
cspec
BP4 Met Computational evidence supports a benign interpretation. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.1066G>C; BayesDel is -0.347259, which is below the BP4_Moderate threshold of -0.008, and SpliceAI predicts no splice effect (max delta score 0.00). REVEL is also low at 0.138.
vcep_pp3_bp4_codes bayesdel spliceai revel cspec
BP5 N/A BP5 is not used for TP53 in this framework.
cspec
BP6 Met Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.
cspec clinvar
BP7 N/A BP7 applies to synonymous or qualifying intronic variants, not to this missense variant.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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