Classification rationale

PM2 BS3BP4BP6 Likely benign

TP53 c.1066G>C

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

PM2 + BS3 + BP4 + BP6 → Likely benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗

3 vcep_functional_worksheetPMID:12826609 ↗cspec ↗

4 vcep_pp3_bp4_codesbayesdelspliceai ↗revelcspec ↗

Gene diagram · NM_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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

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

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.138. BayesDel score = -0.347259.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

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. 9 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:12826609

PMID PMID:12826609 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supports · met

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

20978130 ↗ Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation. ONCOKB

12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. CLINVAR

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