Classification rationale

PM2 BS3BP4BP6 Likely Benign

TP53 c.1066G>C missense · exon 10

PM2 (Supporting): total allele frequency 4.34e-06, below the VCEP <0.00003 threshold. BS3 (Strong): Kato et al. classify p.(Gly356Arg) as fully functional with no loss of function. BP4 (Moderate): BayesDel -0.347 meets the <=-0.008 cutoff; SpliceAI predicts no splicing impact (max delta 0.004). BP6 (Supporting): ClinGen TP53 Variant Curation Expert Panel classified this exact variant as Likely Benign. Overall Likely Benign: PM2 (+1) + BS3 (-4) + BP4 (-1) + BP6 (-1) = -5, within Rule4 (-6 to -2).

PM2 + BS3 + BP4 + BP6 → Likely Benign

Gene diagram · NM_000546.6 · variants mapped to exon structure

TP53 NM_000546.6

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 14 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 Pathogenic

Met (Supporting): total allele frequency 4.34e-06 is below the VCEP threshold of <0.00003 in gnomAD v4.1.

TP53 VCEP v2.4 specifies PM2 at supporting strength for total AF <0.00003; where multiple alleles occur in an ancestry group, that group's AF must be <0.00004, with founder-effect groups ignored.gnomAD v4.1 reports 7/1,613,958 total alleles, AF 4.33716e-06, and no homozygotes.The highest reported eligible continental-subpopulation AF is 5.93229e-06 in European non-Finnish (7/1,179,982 alleles), below 0.00004; grpmax FAF is 2.47e-06.

cspec ↗gnomad_v4 ↗

✓

BS3 strong Benign

Met (Strong): Kato et al. transactivation data classify p.(Gly356Arg) as fully functional with no loss of function, per the TP53 VCEP worksheet.

TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) row for G356R: Kato et al. classification = Functional, LOF status = noLOF, VCEP pre-assigned code = BS3.TP53 VCEP cspec v2.4 BS3 Strong rule: 'Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays' -- satisfied because Kato classifies G356R as Functional/noLOF and no other eligible assay (Funk, Giacomelli, Kotler, Kawaguchi) shows LOF for this variant (all marked NA/not tested).TP53 VCEP cspec BS3 instructionsToUse caveat: do not apply BS3 for protein-level missense assays (Kato/Giacomelli) if PP3 is applied via SpliceAI for the same variant, or if there is RNA-level splicing aberration evidence -- flagged here for cross-check against the in-silico/splicing evidence group, not resolved within this functional group.

cspec ↗

✓

BP4 moderate review Benign

Met (Moderate): BayesDel -0.347 meets the <=-0.008 cutoff, and SpliceAI predicts no splicing impact (max delta 0.004). Flagged for human review: the aGVGD C65 exclusion could not be confirmed.

TP53 VCEP cspec v2.4 BP4 rule: missense variants get BP4_Moderate when BayesDel <= -0.008 irrespective of aGVGD score (except C65, in which case do not apply BP4_Moderate) AND SpliceAI < 0.2 (no predicted splicing differences).Local BayesDel predictor lookup score for this variant is -0.347259 (source: bayesdel), well below the -0.008 BP4_Moderate cutoff.SpliceAI Lookup (source: spliceai) max delta score is 0.004, well under the 0.2 threshold, confirming no predicted splicing impact required for the BP4 missense rule.

cspec ↗spliceai ↗

✓

BP6 supporting Benign

Met (Supporting): the ClinGen TP53 Variant Curation Expert Panel classified this exact variant as Likely Benign.

ClinVar variation 234059 exactly matches NM_000546.6(TP53):c.1066G>C (p.Gly356Arg). Its expert-panel submission is SCV001949906 from the ClinGen TP53 Variant Curation Expert Panel, classified Likely Benign and reviewed by expert panel. Ordinary laboratory submissions and aggregate labels were not used.ClinVar expert panel classification

clinvar ↗

Assessed · not applied · 6 not met · 8 not assessed

Pathogenic

PS1 Not assessed: no other nucleotide change producing the identical p.(Gly356Arg) protein with a Pathogenic classification was identified.

PS2 Not assessed: no de novo occurrence or documented parental testing for this variant is available.

PS3 Not met: Kato et al.

PS4 Not assessed: no qualifying germline proband with this exact variant, phenotype, or cancer-point evidence is documented.

PM1 Not met: codon 356 is not among the VCEP hotspot codons (175, 245, 248, 249, 273, 282) and shows no significant cancerhotspots occurrence.

PM5 Not assessed: no pathogenic variant at codon 356 was identified; known G356A and G356E changes carry benign-leaning classifications.

PP1 Not assessed: no affected relatives with confirmed testing are documented, so cosegregation cannot be established.

PP3 Not met: BayesDel score -0.347 is far below the >=0.16 threshold, and SpliceAI predicts no splicing impact (max delta 0.004).

PP4 Not assessed: no qualifying low-VAF multigene-panel observation of this variant is available.

PP5 Not met: the expert-panel ClinVar assertion for this exact variant is Likely Benign, not Pathogenic or Likely Pathogenic.

Benign

BA1 Not met: maximum continental-subpopulation allele frequency 5.93e-06 is far below the 0.001 BA1 threshold.

BS1 Not met: maximum continental-subpopulation allele frequency 5.93e-06 is below the 0.0003 BS1 threshold.

BS2 Not assessed: no documented count of unrelated women reaching age 60 without cancer is available.

BS4 Not assessed: no affected family members with documented absence of the variant are identified.

N/A · 10 PVS1 · PM3 · PM4 · PM6 · PP2 · 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%

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 (4 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 ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

20978130 ↗ Cancer-associated p53 tetramerization domain mutants: quantitative analysis reve ONCOKB

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

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct t CLINVAR

21519010 ↗ TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. CLINVAR

22186996 ↗ TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. CLINVAR

24356096 ↗ Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics CLINVAR