TP53c.845G>TUncertain significance

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Variant interpretation report

TP53 c.845G>T, p.(Arg282Leu)

NM_000546.5:c.845G>T NP_000537.3:p.(Arg282Leu) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TP53

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (benign) · 2 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0
Other laboratories (ClinVar): 6 Uncertain significance
Pipeline record: 30 May 2026

Evidence considered

View criteria

Applied evidence criteria

PM1 (moderate): This missense variant affects codon 282 (p.Arg282), which is explicitly listed in the TP53 VCEP PM1 rule as a moderate-strength hotspot codon (alongside codons 175, 245, 248, 249, 273). Additionally, the residue is a statistically significant cancer hotspot (cancerhotspots.org), and COSMIC records 10 somatic occurrences at this amino acid change, independently satisfying the PM1_Moderate threshold (≥10 somatic occurrences for the same amino acid change).
PM2 (supporting): This variant is extremely rare in population databases. In gnomAD v4.1, the total allele frequency is 3.10×10⁻⁶ (5/1,613,954 alleles), with a grpmax filtering allele frequency of 7.9×10⁻⁷. The highest subpopulation frequency is in East Asian (2.23×10⁻⁵; 1/44,858 alleles). Both the total AF and subpopulation AF are well below the TP53 VCEP PM2_Supporting cutoff of <0.00003 (0.003%) total and <0.00004 (0.004%) per genetic ancestry group. The variant is absent from gnomAD v2.1. No founder-effect populations are implicated.
PP3 (moderate): Per the TP53 VCEP PP3-BP4-codes worksheet (Supplementary Table S2), this variant is assigned aGVGD Class C65 with BayesDel score 0.360452 and the pre-computed code PP3_moderate. The VCEP PP3 rule specifies that aGVGD Class C65 with BayesDel ≥0.16 qualifies for PP3 at moderate strength. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico assessment proceeds via the missense pathway without splicing considerations. REVEL score (0.898) independently supports a deleterious prediction.
BS3 (strong): Per the TP53 VCEP Functional-worksheet (Supplementary Table S3), the p.Arg282Leu variant is functional in the Kato et al. assay and demonstrates no loss of function in the Giacomelli, Kotler, and Kawaguchi assays (all noLOF). This satisfies the TP53 VCEP BS3_Strong rule: 'Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays.' The variant retains wild-type-like protein function across multiple orthogonal functional assays, providing strong evidence for a benign functional effect.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 1

Pathogenic criteria applied · 3

PM1Moderate

PM1 · moderate

This missense variant affects codon 282 (p.Arg282), which is explicitly listed in the TP53 VCEP PM1 rule as a moderate-strength hotspot codon (alongside codons 175, 245, 248, 249, 273). Additionally, the residue is a statistically significant cancer hotspot (cancerhotspots.org), and COSMIC records 10 somatic occurrences at this amino acid change, independently satisfying the PM1_Moderate threshold (≥10 somatic occurrences for the same amino acid change).

PM2Supporting

PM2 · supporting

This variant is extremely rare in population databases. In gnomAD v4.1, the total allele frequency is 3.10×10⁻⁶ (5/1,613,954 alleles), with a grpmax filtering allele frequency of 7.9×10⁻⁷. The highest subpopulation frequency is in East Asian (2.23×10⁻⁵; 1/44,858 alleles). Both the total AF and subpopulation AF are well below the TP53 VCEP PM2_Supporting cutoff of <0.00003 (0.003%) total and <0.00004 (0.004%) per genetic ancestry group. The variant is absent from gnomAD v2.1. No founder-effect populations are implicated.

PP3Moderate

PP3 · moderate

Per the TP53 VCEP PP3-BP4-codes worksheet (Supplementary Table S2), this variant is assigned aGVGD Class C65 with BayesDel score 0.360452 and the pre-computed code PP3_moderate. The VCEP PP3 rule specifies that aGVGD Class C65 with BayesDel ≥0.16 qualifies for PP3 at moderate strength. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico assessment proceeds via the missense pathway without splicing considerations. REVEL score (0.898) independently supports a deleterious prediction.

Benign criteria applied · 1

BS3Strong

BS3 · strong

Per the TP53 VCEP Functional-worksheet (Supplementary Table S3), the p.Arg282Leu variant is functional in the Kato et al. assay and demonstrates no loss of function in the Giacomelli, Kotler, and Kawaguchi assays (all noLOF). This satisfies the TP53 VCEP BS3_Strong rule: 'Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays.' The variant retains wild-type-like protein function across multiple orthogonal functional assays, providing strong evidence for a benign functional effect.

Recorded classification: Uncertain significance

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM1 moderate (+2) + PM2 supporting (+1) + PP3 moderate (+2) + BS3 strong (-4) = 1 points, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

5 / 1,613,954 alleles

gnomAD v4.1: 5 / 1,613,954 alleles. Recorded AF 3.09798e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

6 reported laboratory submissions

6 Uncertain significance.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

Applied · BS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

10 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53068318, n = 10 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 10 not met · 1 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000546.5:c.845G>T (p.Arg282Leu) is a missense variant in exon 8 of TP53, assessed under the ClinGen TP53 Variant Curation Expert Panel specifications version 2.4.0 (Tavtigian point-based framework).

This variant affects codon 282, a well-established mutational hotspot within the DNA-binding domain explicitly listed in the TP53 VCEP PM1 rule. The residue is a statistically significant cancer hotspot with 10 somatic occurrences in COSMIC, satisfying PM1 at moderate strength (+2 points).

The variant is extremely rare in population databases: gnomAD v4.1 reports an allele frequency of 3.10×10⁻⁶ (5/1,613,954 alleles; grpmax FAF=7.9×10⁻⁷), and it is absent from gnomAD v2.1. All subpopulation frequencies are well below the TP53 VCEP PM2_Supporting cutoff of <0.003%, satisfying PM2 at supporting level (+1 point).

In silico predictors support a deleterious effect: aGVGD Class C65 with BayesDel score 0.360452 and REVEL score 0.898. Per the TP53 VCEP PP3-BP4-codes worksheet, this variant is assigned PP3_moderate (+2 points). SpliceAI predicts no splicing impact (max delta=0.00).

Functional data from the TP53 VCEP Functional-worksheet demonstrates that p.Arg282Leu is functional in the Kato assay and shows no loss of function in Giacomelli, Kotler, and Kawaguchi assays. This satisfies BS3 at strong benign strength (−4 points): functional on Kato AND no LOF by the majority of eligible assays.

The variant has been reported in ClinVar as Uncertain Significance by 6 clinical laboratories and as Uncertain Significance by the ClinGen TP53 Variant Curation Expert Panel (ClinVar ID: 182938). No proband data meeting Li-Fraumeni syndrome criteria was available for PS4 assessment.

No de novo observations, cosegregation data, VAF data, or BS2/BS4 evidence was identified for this variant. PVS1 is not applicable to this missense variant. PS1 has no alternative nucleotide change comparator. PM5 requires curator review of VCEP classifications for comparator codon 282 variants.

Final Tavtigian point total: PM1_Moderate (+2) + PM2_Supporting (+1) + PP3_Moderate (+2) + BS3_Strong (−4) = +1 point. This falls within the Uncertain Significance range (−1 to +5) per the TP53 VCEP v2.4.0 Tavtigian point-based rules. The classification is consistent with the ClinGen TP53 VCEP expert panel determination of Uncertain Significance for this variant.

Met · 4

PM1 ModerateThis missense variant affects codon 282 (p.Arg282), which is explicitly listed in the TP53 VCEP PM1 rule as a moderate-strength hotspot codon (alongside codons 175, 245, 248, 249, 273). Additionally, the residue is a statistically significant cancer hotspot (cancerhotspots.org), and COSMIC records 10 somatic occurrences at this amino acid change, independently satisfying the PM1_Moderate threshold (≥10 somatic occurrences for the same amino acid change). Details ▾Hide ▴

Evidence considered

TP53 VCEP PM1 rule: codon 282 is explicitly listed for PM1_Moderate
Cancer Hotspots: residue 282 is a statistically significant hotspot
COSMIC: 10 somatic occurrences (COSV53068318) — satisfies ≥10 threshold for PM1_Moderate per VCEP

Sources

cspec ↗

PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v4.1, the total allele frequency is 3.10×10⁻⁶ (5/1,613,954 alleles), with a grpmax filtering allele frequency of 7.9×10⁻⁷. The highest subpopulation frequency is in East Asian (2.23×10⁻⁵; 1/44,858 alleles). Both the total AF and subpopulation AF are well below the TP53 VCEP PM2_Supporting cutoff of <0.00003 (0.003%) total and <0.00004 (0.004%) per genetic ancestry group. The variant is absent from gnomAD v2.1. No founder-effect populations are implicated. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF=3.10×10⁻⁶ (5/1
613
954 alleles
0 homozygotes)
grpmax FAF=7.9×10⁻⁷
gnomAD v2.1: absent
East Asian subpopulation: AF=2.23×10⁻⁵ (1/44
858 alleles) — well below VCEP PM2_Supporting cutoff of 0.004% per ancestry group
All AF values far below TP53 VCEP PM2_Supporting threshold of <0.00003 (0.003%)

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

PP3 ModeratePer the TP53 VCEP PP3-BP4-codes worksheet (Supplementary Table S2), this variant is assigned aGVGD Class C65 with BayesDel score 0.360452 and the pre-computed code PP3_moderate. The VCEP PP3 rule specifies that aGVGD Class C65 with BayesDel ≥0.16 qualifies for PP3 at moderate strength. SpliceAI predicts no splicing impact (max delta = 0.00), so the in silico assessment proceeds via the missense pathway without splicing considerations. REVEL score (0.898) independently supports a deleterious prediction. Details ▾Hide ▴

Evidence considered

VCEP PP3-BP4-codes.xlsx: c.845G>T → aGVGD Class C65
BayesDel=0.360452
code=PP3_moderate
BayesDel score 0.360452 (≥0.16 threshold for PP3_Moderate)
REVEL score 0.898 (strongly damaging prediction)
SpliceAI max delta=0.00 (no splicing impact → missense pathway used in VCEP flowchart)

Sources

vcep_pp3_bp4_codesbayesdelrevelspliceai ↗cspec ↗

BS3 StrongPer the TP53 VCEP Functional-worksheet (Supplementary Table S3), the p.Arg282Leu variant is functional in the Kato et al. assay and demonstrates no loss of function in the Giacomelli, Kotler, and Kawaguchi assays (all noLOF). This satisfies the TP53 VCEP BS3_Strong rule: 'Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays.' The variant retains wild-type-like protein function across multiple orthogonal functional assays, providing strong evidence for a benign functional effect. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet: R282L → Kato=Functional
Giacomelli=noLOF
Kotler=noLOF
Kawaguchi=noLOF
code=BS3
Kato functional result + 3/3 non-Kato assays showing noLOF = majority noLOF
Satisfies BS3_Strong per TP53 VCEP: Functional on Kato AND no LOF by majority of eligible assays
OncoKB classification: Likely Neutral — consistent with benign functional interpretation

Sources

vcep_functional_worksheetcspec ↗

Not met · 10 · evaluated, threshold not reached

PS2 No confirmed de novo observation with confirmed maternity/paternity has been identified for this variant. The exploratory search referenced an unverifiable source (PMID not found in PubMed). ClinVar submissions do not include de novo reports for this variant. Details ▾Hide ▴

Evidence considered

Exploratory search alleged a de novo case but cited a non-existent PMID (23456789)
ClinVar submissions (6 clinical laboratories) do not report de novo occurrence
Full-text verification was attempted but publication files contained only Sci-Hub landing pages without actual paper content

Still missing

No verified de novo observation available
if a confirmed de novo case is identified
PS2 may be applicable per VCEP point-based rules (1 pt = Supporting
2-3 pts = Moderate
4-7 pts = Strong
≥8 pts = Very Strong)

Sources

clinvar ↗

PS3 Per the TP53 VCEP Functional-worksheet (Supplementary Table S3), the p.Arg282Leu substitution is functional in the Kato assay and demonstrates no loss of function across Giacomelli, Kotler, and Kawaguchi assays. The pre-assigned VCEP code is BS3 (benign functional evidence), not PS3. The variant retains wild-type-like function, so pathogenic functional evidence (PS3) is not met. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet: R282L → Kato=Functional
Giacomelli=noLOF
Kotler=noLOF
Kawaguchi=noLOF
code=BS3
OncoKB classification: Likely Neutral

Sources

vcep_functional_worksheet

PS4 No verified proband data meeting Li-Fraumeni syndrome criteria is available to assign PS4 points. The ClinGen TP53 Variant Curation Expert Panel classified this variant as Uncertain Significance (ClinVar ID 182938), indicating insufficient proband evidence to support PS4. The exploratory search referenced unverifiable sources. COSMIC reports 10 somatic occurrences, but somatic data does not directly support germline PS4 per VCEP specifications. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification: Uncertain Significance (ClinVarID 182938)
COSMIC: 10 somatic occurrences (COSV53068318) — somatic
not sufficient for germline PS4
No verified proband data with LFS cancer diagnoses available for point calculation

Still missing

If independent probands meeting Chompret or classical LFS criteria are identified
PS4 points may be assignable per VCEP PS4-Points-Table (4 pts per strongly associated LFS cancer
2 pts per moderately associated)

Sources

clinvar ↗

PP1 No verified cosegregation data is available for this variant. The exploratory search referenced an unverifiable source (non-existent PMID). No family studies demonstrating cosegregation of this variant with Li-Fraumeni syndrome phenotypes were identified in the evidence packet. Details ▾Hide ▴

Evidence considered

No verified family segregation studies identified for this variant
Exploratory search cited fabricated PMID (34567890) — not usable

Still missing

If cosegregation data becomes available
PP1 may be applied per VCEP thresholds: ≥7 meioses across >1 family = PP1_Strong
5-6 meioses = PP1_Moderate
3-4 meioses = PP1_Supporting

PP4 PP4 per TP53 VCEP requires observation of the variant at low variant allele fraction (VAF 5-35%) in blood, indicative of somatic mosaicism or clonal hematopoiesis. No VAF data is available for this variant in the evidence packet. This criterion cannot be assessed without allele-specific quantification from clinical testing data. Details ▾Hide ▴

Evidence considered

TP53 VCEP PP4 requires VAF data (5-35% for Supporting
≥2 independent observations at 5-25% for Moderate)
No VAF data available in evidence packet

Still missing

VAF data from clinical testing laboratories would be needed to assess PP4

Sources

cspec ↗

BA1 The variant is extremely rare, not common. gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷, far below the TP53 VCEP BA1 standalone benign threshold of ≥0.001 (0.1%). The variant is absent from gnomAD v2.1. BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF=7.9×10⁻⁷ (BA1 threshold: ≥0.001)
gnomAD v2.1: absent
Total AF=3.10×10⁻⁶ — far below any population frequency threshold

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BS1 The variant's population frequency is too low to meet BS1. gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷, far below the TP53 VCEP BS1_Strong threshold of ≥0.0003 (0.03%). No genetic ancestry group (excluding founder populations) has ≥2 alleles above the BS1 cutoff. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF=7.9×10⁻⁷ (BS1 threshold: ≥0.0003)
East Asian subpopulation: only 1 allele out of 44
858 (AF=2.23×10⁻⁵)
<2 alleles required
No genetic ancestry group meets the ≥0.0003 FAF threshold

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BS2 BS2 per TP53 VCEP requires observations of the variant in unrelated females aged ≥60 years without cancer, from a single source. No such data is available in the evidence packet. gnomAD does not provide age or cancer phenotype data for variant carriers. Details ▾Hide ▴

Evidence considered

No data on cancer-free elderly female carriers available
gnomAD v4.1 has 5 carriers but no phenotype/age data

Still missing

If clinical databases identify ≥2 unrelated cancer-free females ≥60 years carrying this variant
BS2_Supporting may apply

Sources

cspec ↗

BS4 BS4 per TP53 VCEP requires lack of segregation in affected family members (family members diagnosed with LFS-associated cancers who do not carry the variant). No verified segregation data — either for or against — is available for this variant. The exploratory search referenced an unverifiable source. Details ▾Hide ▴

Evidence considered

No verified family segregation data available
Exploratory search cited fabricated PMID (45678901) — not usable

Still missing

Family studies showing non-segregation with LFS cancers would be needed for BS4

Sources

cspec ↗

BP4 The variant's BayesDel score (0.360452) is above the BP4 threshold (<0.16). Per the TP53 VCEP PP3-BP4-codes worksheet, this variant is assigned PP3_moderate (not BP4). The aGVGD class is C65, which per the VCEP flowchart precludes BP4 application. SpliceAI predicts no splicing impact (max delta=0.00), but the missense in silico scores are in the pathogenic range, not benign. Details ▾Hide ▴

Evidence considered

BayesDel = 0.360452 (BP4 requires ≤0.16
or <0.16 & >-0.008 for BP4_Supporting)
aGVGD Class C65 — VCEP specifies C65 precludes BP4
VCEP PP3-BP4-codes.xlsx pre-assigned code is PP3_moderate
not BP4

Sources

vcep_pp3_bp4_codesbayesdelcspec ↗

Not assessed · 1 · no assessment recorded

PM5 Multiple different missense variants exist at codon 282 (R282G, R282P, R282W — all assigned PS3 in the VCEP functional worksheet). However, PM5 per TP53 VCEP requires comparator variants to be previously classified as Pathogenic or Likely Pathogenic according to the TP53 VCEP specifications. Without access to the VCEP classification database to confirm the final classification status of comparator variants at codon 282 (as distinct from functional evidence alone), PM5 cannot be definitively applied. This requires curator review of VCEP classifications for R282G, R282P, R282W, and other codon 282 variants. Details ▾Hide ▴

Evidence considered

Multiple missense variants at codon 282 in VCEP functional worksheet: R282G (PS3)
R282P (PS3)
R282W (PS3)
TP53 VCEP PM5 requires comparator to be classified as P/LP per VCEP specifications
not merely have PS3 evidence

Still missing

Need to verify VCEP final classification (not just functional code) for codon 282 comparator variants — if ≥2 are classified Pathogenic
PM5_Strong applies
if 1 Pathogenic
PM5_Moderate
if 1 Likely Pathogenic with clinical data
PM5_Supporting

Sources

cspec ↗vcep_functional_worksheet

Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense variant; PVS1 is reserved for null variants (nonsense, frameshift, canonical splice site) per both ACMG/AMP 2015 and TP53 VCEP v2.4.0 PVS1 flowchart. This variant does not fall into any PVS1 bucket: it is neither a null variant nor a canonical splice alteration. Details ▾Hide ▴

Evidence considered

Missense variant at codon 282 (Arg→Leu) — not a null variant
pvs1_variant_assessment.json confirms variant_bucket='other'
no PVS1 strength assigned
TP53 VCEP PVS1 flowchart applies only to nonsense
frameshift
canonical splice
initiation codon
and CNV variants

Sources

cspec ↗pvs1_generic_framework ↗

PS1 N/APS1 requires a different nucleotide change producing the same amino acid substitution (p.Arg282Leu) previously classified as P/LP per VCEP. The codon is CGG (Arg). c.845G>A yields CAG (Gln) and c.845G>C yields CCG (Pro); no alternative nucleotide substitution at c.845 produces leucine. Therefore no same-amino-acid comparator exists. Details ▾Hide ▴

Evidence considered

Codon 282 = CGG (Arg). c.845G>T = CTG (Leu). c.845G>A = CAG (Gln). c.845G>C = CCG (Pro).
No alternative nucleotide change produces p.Arg282Leu.

Sources

cspec ↗

PM3 VCEPRecessive disorder criterion — not applicable to TP53, a tumor suppressor with autosomal dominant inheritance. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPNon-repeat in-frame deletion/insertion criterion — this is a missense substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion is not used for TP53 variant interpretation per ClinGen SVI VCEP Review Committee guidance. Details ▾Hide ▴

Evidence considered

TP53 VCEP: PM6 applicability = Not Applicable

Sources

cspec ↗

PP2 VCEPPP2 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion (missense in gene with low rate of benign missense variation) is not used for TP53 per ClinGen SVI guidance. Details ▾Hide ▴

Evidence considered

TP53 VCEP: PP2 applicability = Not Applicable

Sources

cspec ↗

PP5 VCEPPP5 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Evidence considered

TP53 VCEP: PP5 applicability = Not Applicable

Sources

cspec ↗

BP1 VCEPBP1 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion (missense variant in a gene where primarily truncating variants cause disease) is not used for TP53 per ClinGen SVI guidance. Details ▾Hide ▴

Evidence considered

TP53 VCEP: BP1 applicability = Not Applicable

Sources

cspec ↗

BP2 VCEPBP2 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion (observed in trans with a pathogenic variant for a fully penetrant dominant disorder) is not used for TP53. Details ▾Hide ▴

Evidence considered

TP53 VCEP: BP2 applicability = Not Applicable

Sources

cspec ↗

BP3 VCEPIn-frame deletions/insertions in repetitive region — not relevant to a single-nucleotide missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP5 VCEPBP5 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion (variant found in a case with an alternate molecular basis for disease) is not used for TP53. Details ▾Hide ▴

Evidence considered

TP53 VCEP: BP5 applicability = Not Applicable

Sources

cspec ↗

BP6 VCEPBP6 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications. This criterion (reputable source reports variant as benign) is not for use per ClinGen SVI VCEP Review Committee guidance. Details ▾Hide ▴

Evidence considered

TP53 VCEP: BP6 applicability = Not Applicable

Sources

cspec ↗

BP7 N/ABP7 is applicable only to synonymous (silent) and intronic variants per the TP53 VCEP PP3/BP4/BP7 flowchart. This is a missense variant (c.845G>T, p.Arg282Leu) and does not qualify for BP7 evaluation. Details ▾Hide ▴

Evidence considered

Variant type: missense
not synonymous or intronic
VCEP BP7 flowchart applies to synonymous and intronic variants only

Sources

cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

PS5 N/APS5 is not used by the TP53 VCEP and is not included in the v2.4.0 specifications. Per ClinGen SVI recommendations, this criterion has been functionally superseded and is not applied in current variant interpretation frameworks. Details ▾Hide ▴

Evidence considered

PS5 is not present in TP53 VCEP v2.4.0 criteria set

Sources

cspec ↗

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.845G>T
Protein (HGVS p.): NP_000537.3:p.(Arg282Leu)
GRCh38: chr17:7673775 C>A
GRCh37: chr17:7577093 C>A
ClinVar: 182938
COSMIC: COSV53068318

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.

TP53NM_000546.5

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in TP53 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 5 / 1,613,954 alleles AF 3.1e-06 · 0 homozygotes · FAF 7.9e-07

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,613,954 alleles · 0 hom · FAF 7.9e-07

East Asian1 / 44,858	2.2e-05
European (non-Finnish)4 / 1,180,030	3.4e-06

0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.09798e-06; MAF= 0.00031%, 5/1613954 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22926e-05; MAF= 0.00223%, 1/44858 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.898
BayesDel: 0.360

How the predictions were used

Evidence considered

VCEP PP3-BP4-codes.xlsx: c.845G>T → aGVGD Class C65
BayesDel=0.360452
code=PP3_moderate
BayesDel score 0.360452 (≥0.16 threshold for PP3_Moderate)
REVEL score 0.898 (strongly damaging prediction)
SpliceAI max delta=0.00 (no splicing impact → missense pathway used in VCEP flowchart)

Sources

vcep_pp3_bp4_codesbayesdelrevelspliceai ↗cspec ↗

Evidence considered

BayesDel = 0.360452 (BP4 requires ≤0.16
or <0.16 & >-0.008 for BP4_Supporting)
aGVGD Class C65 — VCEP specifies C65 precludes BP4
VCEP PP3-BP4-codes.xlsx pre-assigned code is PP3_moderate
not BP4

Sources

vcep_pp3_bp4_codesbayesdelcspec ↗

Evidence considered

Variant type: missense
not synonymous or intronic
VCEP BP7 flowchart applies to synonymous and intronic variants only

Sources

cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.898. BayesDel score = 0.360452.

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

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

Kato S et al. · 2003

No paper-specific finding is recorded.

PMID 12826609 ↗
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E et al. · 2018

No paper-specific finding is recorded.

PMID 29979965 ↗
Mutational processes shape the landscape of TP53 mutations in human cancer.

Giacomelli AO et al. · 2018

No paper-specific finding is recorded.

PMID 30224644 ↗
p53 mutations as tumor markers in fine needle aspirates of palpable breast masses.

No paper-specific finding is recorded.

PMID 12365217 ↗
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

No paper-specific finding is recorded.

PMID 26619011 ↗
TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.

No paper-specific finding is recorded.

PMID 27328919 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,613,954 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 6 Uncertain significance Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 182938)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.898. BayesDel score = 0.360452.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53068318, n = 10 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.