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.1 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.2 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 PS3.3 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 0.138.4
Final classification
Likely benign
PM2BS3BP4BP6
TP53
c.1066G>C
p.Gly356Arg
This variant
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.
TP53 ClinGen VCEP v2.4.0 Tavtigian point-based framework from the CSPEC final-classification ruleset; PM2_Supporting (+1), BS3_Strong (-4), BP4_Moderate (-2), and BP6_Supporting_Benign (-1) yield a total of -6 points.
Classification rationale
PM2
BS3BP4BP6
Likely benign
TP53 c.1066G>C
PM2 + BS3 + BP4 + BP6
→
Likely benign
3
vcep_functional_worksheetPMID:12826609 ↗cspec ↗
4
vcep_pp3_bp4_codesbayesdelspliceai ↗revelcspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
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 v4.1 total AF 4.33716e-06grpmax FAF 2.47e-06best subpopulation AF 5.93229e-06.
BS3
strong
review
Benign
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.
Functional worksheet row: G356RKato class FunctionalGiacomelli class noLOF
BP4
moderate
review
Benign
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.
PP3/BP4 worksheet row: c.1066G>CClass C0BayesDel -0.347259
Assessed · not applied
· 7 not met · 6 not assessed
Pathogenic
PS1
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.
PS2
No confirmed de novo observation with sufficient parental testing and phenotype scoring was identified for this variant.
PS3
Available TP53 functional evidence does not support a damaging effect.
PS4
No phenotype-weighted Li-Fraumeni syndrome proband data were identified to support PS4, although this criterion remains potentially assessable only after PM2 is met.
PM1
This codon is not one of the TP53 codons explicitly specified for PM1, and no Cancer Hotspots hotspot row was identified for p.Gly356Arg.
PM5
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.
PP1
No informative cosegregation data were identified for this variant.
PP3
Available computational evidence does not support a damaging effect.
PP4
No low-variant-allele-fraction constitutional mosaicism evidence or other TP53-specific PP4 clinical context was identified for this variant.
Benign
BA1
Population data do not reach the TP53 VCEP BA1 threshold.
BS1
Population data do not reach the TP53 VCEP BS1 threshold.
BS2
No single-source dataset of unaffected older female carriers was identified for this variant.
BS4
No informative lack-of-segregation data were identified for this variant.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.33716e-06; MAF= 0.00043%, 7/1613958 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93229e-06; MAF= 0.00059%, 7/1179982 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98721e-06; MAF= 0.00040%, 1/250802 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82208e-06; MAF= 0.00088%, 1/113352 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 7 / 1,613,958
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
European (non-Finnish) 7 / 1,179,982 |
0.00059% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,802
0 hom
0 hom
European (non-Finnish) 1 / 113,352 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 234059)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.138. BayesDel score = -0.347259.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & references.
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
20978130 ↗
Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation.
ONCOKB
21343334 ↗
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.
CLINVAR
21519010 ↗
TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.
CLINVAR
24356096 ↗
Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
25952993 ↗
TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases.
CLINVAR
26230955 ↗
TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR