TP53c.473G>TPathogenic

Print report

Variant interpretation report

TP53 c.473G>T, p.(Arg158Leu)

NM_000546.6:c.473G>T NP_000537.3:p.(Arg158Leu) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

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: 2 strong (pathogenic) · 2 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0
Other laboratories (ClinVar): 7 Pathogenic · 2 Likely pathogenic
Pipeline record: 22 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): R158L is non-functional on Kato et al. (PMID:12826609) transactivation assay data AND demonstrates loss of function (LOF) across all other eligible functional assays (Funk, Giacomelli, Kotler), meeting the TP53 VCEP rule for PS3 (Strong): 'Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.' Functional assignment confirmed in VCEP Functional-worksheet.xlsx Supplementary Table S3. Additional functional evidence from Baroni et al. (PMID:15037740) demonstrates R158L has no detectable transcriptional activity in yeast and mammalian reporter gene assays, with partial rescue by the 235-239-240 intragenic suppressor motif.
PM1 (moderate): Codon 158 is not among the VCEP-listed hotspot codons (175, 245, 248, 249, 273, 282) for the codon-position PM1 rule. However, the variant has 181 somatic occurrences in COSMIC (COSV52676395), far exceeding the VCEP threshold of ≥10 somatic occurrences for the same amino acid change (R158L), meeting PM1 at Moderate strength per VCEP rule: 'This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥10 somatic occurrences for the same amino acid change.' The residue also lies in a statistically significant hotspot.
PM2 (supporting): Variant is extremely rare in population databases. gnomAD v2.1: AF = 3.98e-06 (1/251,268 alleles, 0 homozygotes). gnomAD v4.1: AF = 6.20e-07 (1/1,614,128 alleles, 0 homozygotes). Absent from gnomAD-Canada v1.0. Both frequencies are far below the VCEP PM2_Supporting threshold of <0.00003 (0.003%). Single-allele observations across populations with no genetic ancestry group exceeding the 0.00004 multi-allele threshold.
PM5 (strong): Although the automated PM5 pipeline misclassified this variant as non-missense, manual review confirms c.473G>T is a missense variant producing p.Arg158Leu. Per the VCEP Functional-worksheet.xlsx, at least three different missense variants at codon 158 carry PS3 (Strong) assignments: R158G (PS3), R158H (PS3), and R158P (PS3). These represent ≥2 different missense variants at the same amino acid residue previously determined to be pathogenic per VCEP specifications, meeting PM5 at Strong strength per VCEP rule: 'Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the TP53 VCEP's specifications have been seen before.'
PP3 (moderate): Per VCEP PP3-BP4-codes.xlsx Supplementary Table S2: c.473G>T is assigned PP3_moderate. The variant has aGVGD Class C65 and BayesDel score 0.575563 (≥0.16), meeting the VCEP rule for PP3_Moderate: 'aGVGD Class C65 and BayesDel score ≥0.16.' REVEL score is 0.891 (strongly pathogenic prediction). SpliceAI max delta is 0.00 (no predicted splicing impact).
PP5 (supporting): Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

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: 6 Benign evidence criteria: 0

Pathogenic criteria applied · 6

PS3Strong

PS3 · strong

R158L is non-functional on Kato et al. (PMID:12826609) transactivation assay data AND demonstrates loss of function (LOF) across all other eligible functional assays (Funk, Giacomelli, Kotler), meeting the TP53 VCEP rule for PS3 (Strong): 'Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.' Functional assignment confirmed in VCEP Functional-worksheet.xlsx Supplementary Table S3. Additional functional evidence from Baroni et al. (PMID:15037740) demonstrates R158L has no detectable transcriptional activity in yeast and mammalian reporter gene assays, with partial rescue by the 235-239-240 intragenic suppressor motif.

PM1Moderate

PM1 · moderate

Codon 158 is not among the VCEP-listed hotspot codons (175, 245, 248, 249, 273, 282) for the codon-position PM1 rule. However, the variant has 181 somatic occurrences in COSMIC (COSV52676395), far exceeding the VCEP threshold of ≥10 somatic occurrences for the same amino acid change (R158L), meeting PM1 at Moderate strength per VCEP rule: 'This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥10 somatic occurrences for the same amino acid change.' The residue also lies in a statistically significant hotspot.

PM2Supporting

PM2 · supporting

Variant is extremely rare in population databases. gnomAD v2.1: AF = 3.98e-06 (1/251,268 alleles, 0 homozygotes). gnomAD v4.1: AF = 6.20e-07 (1/1,614,128 alleles, 0 homozygotes). Absent from gnomAD-Canada v1.0. Both frequencies are far below the VCEP PM2_Supporting threshold of <0.00003 (0.003%). Single-allele observations across populations with no genetic ancestry group exceeding the 0.00004 multi-allele threshold.

PM5Strong

PM5 · strong

Although the automated PM5 pipeline misclassified this variant as non-missense, manual review confirms c.473G>T is a missense variant producing p.Arg158Leu. Per the VCEP Functional-worksheet.xlsx, at least three different missense variants at codon 158 carry PS3 (Strong) assignments: R158G (PS3), R158H (PS3), and R158P (PS3). These represent ≥2 different missense variants at the same amino acid residue previously determined to be pathogenic per VCEP specifications, meeting PM5 at Strong strength per VCEP rule: 'Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the TP53 VCEP's specifications have been seen before.'

PP3Moderate

PP3 · moderate

Per VCEP PP3-BP4-codes.xlsx Supplementary Table S2: c.473G>T is assigned PP3_moderate. The variant has aGVGD Class C65 and BayesDel score 0.575563 (≥0.16), meeting the VCEP rule for PP3_Moderate: 'aGVGD Class C65 and BayesDel score ≥0.16.' REVEL score is 0.891 (strongly pathogenic prediction). SpliceAI max delta is 0.00 (no predicted splicing impact).

PP5Supporting

PP5 · supporting

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM1 moderate (+2) + PM2 supporting (+1) + PM5 strong (+4) + PP3 moderate (+2) + PP5 supporting (+1) = 14 points, which maps to Pathogenic.

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

1 / 1,614,128 alleles

gnomAD v4.1: 1 / 1,614,128 alleles. Recorded AF 6.1953e-07. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97981e-06; MAF= 0.00040%, 1/251268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15991e-05; MAF= 0.00616%, 1/16234 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

9 reported laboratory submissions

7 Pathogenic · 2 Likely pathogenic.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

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

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

181 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52676395, n = 181 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.

27 criteria with recorded statuses: 6 met · 4 not met · 7 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 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

PS3 (Strong): R158L is non-functional on Kato et al. transactivation assay and demonstrates loss of function across all eligible functional assays (Funk, Giacomelli, Kotler), meeting the VCEP rule for PS3 at Strong strength.

PM5 (Strong): At least three different missense variants at codon 158 (R158G, R158H, R158P) carry PS3 assignments per the VCEP Functional-worksheet, meeting the VCEP rule for PM5 at Strong strength (≥2 different pathogenic missense variants at the same residue).

PM1 (Moderate): The variant has 181 somatic occurrences in COSMIC, exceeding the VCEP threshold of ≥10 somatic occurrences for the same amino acid change, meeting PM1 at Moderate strength.

PP3 (Moderate): Per VCEP PP3-BP4-codes.xlsx, c.473G>T is assigned PP3_moderate (aGVGD Class C65, BayesDel 0.576, REVEL 0.891).

PM2 (Supporting): Variant is extremely rare in gnomAD (v2.1: 1/251,268; v4.1: 1/1,614,128), far below the VCEP PM2_Supporting threshold of <0.003%.

PP5 (Supporting): The ClinGen TP53 VCEP has classified this variant as Pathogenic (ClinVar Variation ID 528248, expert panel reviewed).

BA1, BS1, BS3, BP4 not met: Population frequencies are far below benign thresholds. Functional data demonstrate complete loss of function, contradicting BS3. In silico predictions are decisively pathogenic, contradicting BP4.

PVS1, PS1, PS2, PS4, PS5, PM6, PP1, PP2, PP4, BS2, BS4, BP1, BP2, BP3, BP5, BP6, BP7 not applicable or not assessed due to variant type, VCEP rules, or absence of required evidence.

Met · 6

PS3 StrongR158L is non-functional on Kato et al. (PMID:12826609) transactivation assay data AND demonstrates loss of function (LOF) across all other eligible functional assays (Funk, Giacomelli, Kotler), meeting the TP53 VCEP rule for PS3 (Strong): 'Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.' Functional assignment confirmed in VCEP Functional-worksheet.xlsx Supplementary Table S3. Additional functional evidence from Baroni et al. (PMID:15037740) demonstrates R158L has no detectable transcriptional activity in yeast and mammalian reporter gene assays, with partial rescue by the 235-239-240 intragenic suppressor motif. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet: R158L = PS3 (Non-functional on Kato
LOF on Funk/Giacomelli/Kotler)
Baroni et al. 2004: R158L shows 0% WT transcriptional activity in yeast and H1299 mammalian assays
partial rescue to ~50% on p21 promoter with suppressor motif

Sources

PMID:12826609 ↗PMID:15037740 ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes

PM1 ModerateCodon 158 is not among the VCEP-listed hotspot codons (175, 245, 248, 249, 273, 282) for the codon-position PM1 rule. However, the variant has 181 somatic occurrences in COSMIC (COSV52676395), far exceeding the VCEP threshold of ≥10 somatic occurrences for the same amino acid change (R158L), meeting PM1 at Moderate strength per VCEP rule: 'This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥10 somatic occurrences for the same amino acid change.' The residue also lies in a statistically significant hotspot. Details ▾Hide ▴

Evidence considered

COSMIC: 181 somatic occurrences (COSV52676395)
Hotspots: residue in statistically significant hotspot
VCEP PM1 rule: ≥10 somatic occurrences = Moderate

Sources

cspec ↗

PM2 SupportingVariant is extremely rare in population databases. gnomAD v2.1: AF = 3.98e-06 (1/251,268 alleles, 0 homozygotes). gnomAD v4.1: AF = 6.20e-07 (1/1,614,128 alleles, 0 homozygotes). Absent from gnomAD-Canada v1.0. Both frequencies are far below the VCEP PM2_Supporting threshold of <0.00003 (0.003%). Single-allele observations across populations with no genetic ancestry group exceeding the 0.00004 multi-allele threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 1/251
268 (AF 3.98e-06)
gnomAD v4.1: 1/1
614
128 (AF 6.20e-07)
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

PM5 StrongAlthough the automated PM5 pipeline misclassified this variant as non-missense, manual review confirms c.473G>T is a missense variant producing p.Arg158Leu. Per the VCEP Functional-worksheet.xlsx, at least three different missense variants at codon 158 carry PS3 (Strong) assignments: R158G (PS3), R158H (PS3), and R158P (PS3). These represent ≥2 different missense variants at the same amino acid residue previously determined to be pathogenic per VCEP specifications, meeting PM5 at Strong strength per VCEP rule: 'Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the TP53 VCEP's specifications have been seen before.' Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet: R158G = PS3
R158H = PS3
R158P = PS3 (all different nucleotide changes at same residue)
VCEP PM5 rule: ≥2 different pathogenic missense variants at same residue = Strong

Sources

vcep_functional_worksheetcspec ↗

PP3 ModeratePer VCEP PP3-BP4-codes.xlsx Supplementary Table S2: c.473G>T is assigned PP3_moderate. The variant has aGVGD Class C65 and BayesDel score 0.575563 (≥0.16), meeting the VCEP rule for PP3_Moderate: 'aGVGD Class C65 and BayesDel score ≥0.16.' REVEL score is 0.891 (strongly pathogenic prediction). SpliceAI max delta is 0.00 (no predicted splicing impact). Details ▾Hide ▴

Evidence considered

VCEP PP3-BP4-codes.xlsx: c.473G>T = PP3_moderate
BayesDel: 0.575563 (≥0.16)
aGVGD: Class C65
REVEL: 0.891
SpliceAI: max delta 0.00 (no splicing impact)

Sources

vcep_pp3_bp4_codesbayesdelrevelspliceai ↗cspec ↗

PP5 SupportingExpert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinGen TP53 VCEP classification: Pathogenic (expert panel reviewed)
ClinVar: 7 Pathogenic + 2 Likely pathogenic submissions
ClinVar expert panel classification

Sources

clinvar ↗cspec ↗

Not met · 4 · evaluated, threshold not reached

BA1 gnomAD allele frequencies are far below the VCEP BA1 threshold of ≥0.001 (0.1%) FAF in any continental subpopulation. gnomAD v2.1 max subpopulation AF: 6.16e-05 (African/African American). gnomAD v4.1 max subpopulation AF: 8.47e-07 (European non-Finnish). Only single-allele observations in any population; no subpopulation exceeds the BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max pop AF: 6.16e-05 (≪ 0.001)
gnomAD v4.1 max pop AF: 8.47e-07 (≪ 0.001)

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 gnomAD allele frequencies are far below the VCEP BS1 threshold of FAF ≥0.0003 (0.03%) in any continental subpopulation. No subpopulation has sufficient allele count or frequency to meet BS1. The single-allele observations in gnomAD are consistent with a rare pathogenic variant, not a benign polymorphism. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max pop AF: 6.16e-05 (≪ 0.0003)
gnomAD v4.1 max pop AF: 8.47e-07 (≪ 0.0003)

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS3 BS3 requires functional studies showing no damaging effect on protein function. This is contradicted by the VCEP Functional-worksheet.xlsx, which assigns PS3 (Strong) to R158L based on non-functional status in Kato et al. assay and LOF across all other eligible assays (Funk, Giacomelli, Kotler). BS3 is explicitly not met because functional evidence demonstrates complete loss of function. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet: R158L = PS3 (Non-functional on Kato
LOF on all other assays)
BS3 requires functional/no LOF
which is contradicted

Sources

vcep_functional_worksheetPMID:12826609 ↗PMID:15037740 ↗

BP4 BP4 requires BayesDel score ≤ -0.008 (BP4_Moderate) or < 0.16 and > -0.008 (BP4_Supporting) with no predicted splicing impact. The variant has BayesDel 0.575563 (≥0.16) and aGVGD Class C65, which triggers PP3_moderate per VCEP PP3-BP4-codes.xlsx. BP4 is contradicted by the in silico evidence. SpliceAI delta = 0.00 indicates no splicing impact, but the missense prediction scores are decisively pathogenic. Details ▾Hide ▴

Evidence considered

VCEP PP3-BP4-codes.xlsx: PP3_moderate assigned (not BP4)
BayesDel: 0.575563 (≥0.16
outside BP4 range)
SpliceAI: 0.00 (no splicing impact)

Sources

vcep_pp3_bp4_codesbayesdelspliceai ↗

Not assessed · 7 · no assessment recorded

PS1 PS1 requires a different nucleotide change producing the same p.Arg158Leu amino acid change that has been previously established as pathogenic. No such comparator variant was identified in the evidence reviewed. The variant c.473G>T is a single nucleotide substitution (G→T at position 473); no other nucleotide change producing p.Arg158Leu (e.g., at c.472 or c.474) was found with a confirmed VCEP pathogenic classification. Details ▾Hide ▴

Still missing

No same-amino-acid different-nucleotide comparator variant identified

PS2 No de novo observation data for NM_000546.6:c.473G>T was identified in the evidence reviewed. PS2 requires confirmed de novo occurrence with maternity/paternity confirmation. The VCEP PS2 point system requires proband cancer phenotype scoring (LFS-associated cancers), but no proband-level clinical data were available. Details ▾Hide ▴

Still missing

No de novo observation data available
No proband-level phenotype data

PS4 PS4 requires proband-level case data with Li-Fraumeni syndrome cancer phenotype scoring per the VCEP PS4-Points-Table. No individual proband phenotype data (cancer types, ages of onset, family history) were available in the evidence reviewed. Although the variant is well-established in ClinVar and somatic databases, case-control prevalence comparison data for germline PS4 assessment were not provided. Details ▾Hide ▴

Still missing

No proband-level cancer phenotype data for PS4 point calculation
No case-control prevalence data

PP1 No cosegregation data were available in the evidence reviewed. PP1 requires observation of variant cosegregation with LFS-associated cancers across multiple meioses (VCEP thresholds: Supporting = 3-4 meioses, Moderate = 5-6 meioses, Strong = ≥7 meioses across >1 family). Details ▾Hide ▴

Still missing

No cosegregation data available

PP4 PP4 per VCEP requires variant allele fraction (VAF) data: Moderate = ≥2 independent observations with VAF 5-25%, Supporting = observation with VAF 5-35%. No VAF or patient phenotype data were available in the evidence reviewed. VCEP PP4 is specifically designed to address clonal hematopoiesis concerns in TP53 by requiring low VAF documentation. Details ▾Hide ▴

Still missing

No VAF data available
No patient phenotype specificity data

BS2 BS2 per VCEP requires observation in unrelated females who have reached ≥60 years of age without cancer. No such data were available in the evidence reviewed. VCEP thresholds: Strong = ≥8, Moderate = 4-7, Supporting = 2-3 unrelated females ≥60 years without cancer, all from a single source. Details ▾Hide ▴

Still missing

No healthy elderly female carrier data available

BS4 BS4 requires lack of segregation in affected family members with LFS-associated cancers. No segregation data were available in the evidence reviewed. Details ▾Hide ▴

Still missing

No segregation data available

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 is not applicable to missense variants. The TP53 VCEP PVS1 decision tree (PVS1-Flowchart.pdf) applies only to null variants: nonsense, frameshift, canonical ±1,2 splice sites, initiation codon variants, CNVs, and single/multi-exon deletions. c.473G>T is a missense substitution (p.Arg158Leu) and does not fall into any PVS1-eligible variant bucket. Details ▾Hide ▴

Evidence considered

PVS1 decision tree limited to null variant classes
missense variants excluded

Sources

cspec ↗vcep_pvs1_flowchart

PM6 VCEPPM6 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0 and is not used for TP53 variant classification under this framework. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPPP2 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0. The VCEP does not use PP2 (missense variant in a gene with low rate of benign missense variation) for TP53 classification. Details ▾Hide ▴

Sources

cspec ↗

BP1 VCEPBP1 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0. Details ▾Hide ▴

Sources

cspec ↗

BP2 VCEPBP2 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0. Details ▾Hide ▴

Sources

cspec ↗

BP3 VCEPBP3 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0. Details ▾Hide ▴

Sources

cspec ↗

BP5 VCEPBP5 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0. Details ▾Hide ▴

Sources

cspec ↗

BP6 VCEPBP6 is designated as Not Applicable by the TP53 VCEP specifications v2.4.0. Details ▾Hide ▴

Sources

cspec ↗

BP7 N/ABP7 applies only to synonymous (silent) variants or intronic variants outside the core splice motif per VCEP. c.473G>T is a missense variant (p.Arg158Leu) and does not qualify for BP7 assessment. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 limited to synonymous/intronic variants per VCEP

Sources

cspec ↗

PS5 N/APS5 is not a recognized criterion in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868) nor in the TP53 VCEP specifications v2.4.0. Standard pathogenic strong criteria are PS1-PS4. No PS5 criterion exists for adjudication. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: TP53
Transcript: NM_000546.6
Coding (HGVS c.): NM_000546.6:c.473G>T
Protein (HGVS p.): NP_000537.3:p.(Arg158Leu)
GRCh38: chr17:7675139 C>A
GRCh37: chr17:7578457 C>A
ClinVar: 633445, 528248, 568285, 246118
COSMIC: COSV52676395

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.

TP53NM_000546.6

Fetching transcript structure from UCSC…

Exons

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Transcript span

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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 1 / 1,614,128 alleles AF 6.2e-07 · 0 homozygotes

gnomAD v2.1 1 / 251,268 alleles AF 3.98e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,128 alleles · 0 hom

European (non-Finnish)1 / 1,180,034

8.5e-07

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,268 alleles · 0 hom

African/African American1 / 16,234

6.2e-05

0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.1953e-07; MAF= 0.00006%, 1/1614128 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47433e-07; MAF= 0.00008%, 1/1180034 alleles, homozygotes = 0).

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.891
BayesDel: 0.576

How the predictions were used

Evidence considered

VCEP PP3-BP4-codes.xlsx: c.473G>T = PP3_moderate
BayesDel: 0.575563 (≥0.16)
aGVGD: Class C65
REVEL: 0.891
SpliceAI: max delta 0.00 (no splicing impact)

Sources

vcep_pp3_bp4_codesbayesdelrevelspliceai ↗cspec ↗

Evidence considered

VCEP PP3-BP4-codes.xlsx: PP3_moderate assigned (not BP4)
BayesDel: 0.575563 (≥0.16
outside BP4 range)
SpliceAI: 0.00 (no splicing impact)

Sources

vcep_pp3_bp4_codesbayesdelspliceai ↗

Evidence considered

Missense variant
BP7 limited to synonymous/intronic variants per VCEP

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.891. BayesDel score = 0.575563.

6 paper records listed. 2 cited in the classification.

Cited in the classification

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

Kato S et al. · 2003 Jul 8

Kato et al. performed high-resolution missense mutation analysis of p53 using a yeast-based transactivation assay across 2,314 p53 mutants representing all possible amino acid substitutions. The paper describes the functional assay system and structure-function relationships but does not list individual variant results in the main text. The VCEP Functional-worksheet.xlsx derives R158L functional data (Non-functional) from this paper's supplementary data.
→ PS3 Does not name this variant
PMID 12826609 ↗
Source detail

Location Functional data for R158L in supplementary materials (not in main text body); VCEP Functional-worksheet.xlsx cites Kato et al. as the source of Non-functional classification.

Context Yeast-based p53 transactivation assay; p53 mutants expressed in S. cerevisiae reporter strain, assessed across 8 p53 response elements
A global suppressor motif for p53 cancer mutants.

Baroni TE et al. · 2004 Apr 6

R158L was identified as one of the 30 most common p53 cancer mutants and functionally characterized. R158L showed no detectable transcriptional activity in both yeast and mammalian (H1299) reporter gene assays. The 235-239-240 global suppressor motif partially rescued R158L function: ~20% of WT activity on single p53 DNA-binding sites, ~50% on the p21 promoter, and 65-125% of WT p53 activity in apoptosis assays.
→ PS3 Names this variant
PMID 15037740 ↗
Source detail

Four mutants, R158L, V173M, Y205C, and Y220C, in combination with suppressor amino acids, showed only 20% of WT p53 activity.

Location Abstract; Results (Table 2, entry 27-30); Figure 2 (mammalian reporter assay); Figure 3 (p21 promoter assay); Figure 4 (apoptosis assay)

Context Luciferase reporter gene assays in H1299 (p53-null lung adenocarcinoma) cells; p21 promoter reporter; apoptosis assays in baby hamster kidney cells; yeast p53 functional assay in S. cerevisiae strain RBy377

Other recorded publications

Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.

Dearth LR et al. · 2007

Dearth et al. characterized full-length p53 mutants for dominant-negative effects on wild-type p53. The study focused on common hotspot mutants (R175H, G245S, R248W, R273H, R282W) and their dominant-negative properties. NM_000546.6:c.473G>T (p.Arg158Leu) was not specifically studied in this paper.
Does not name this variant
PMID 16861262 ↗
Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study.

Wasserman et al. analyzed TP53 mutation prevalence and functional consequences in 88 children with adrenocortical carcinoma. The study identified 34 germline TP53 variants but R158L (NM_000546.6:c.473G>T) was not among the variants detected in this pediatric ACC cohort. R158H was identified in one family (maternal inheritance, 16.05% median activity per Kato et al.).
Does not name this variant
PMID 25584008 ↗
Quoted passage
Varley et al identified mutations in 10 of 12 children with ACC. This series was enriched for two alleles, P152L (n = 5) and R158H (n = 3).
Table 2 (Pedigree No. 21: R158H, not R158L)
Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions.

Smith PD et al. · 1999

Smith et al. characterized novel p53 mutants selected in BRCA-associated tumors. The study identified p53 mutants that dissociate transformation suppression from other wild-type p53 functions. NM_000546.6:c.473G>T (p.Arg158Leu) was not among the variants characterized in this paper.
Does not name this variant
PMID 10229196 ↗
Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome.

Tabori U et al. · 2007

Tabori et al. investigated the association between telomere length and age of cancer onset in Li-Fraumeni syndrome. The study focused on telomere biology as a modifier of cancer risk in TP53 mutation carriers but did not characterize specific TP53 variants. NM_000546.6:c.473G>T (p.Arg158Leu) was not specifically studied.
Does not name this variant
PMID 17308077 ↗

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

gnomAD v4.1 1 / 1,614,128 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 7 Pathogenic · 2 Likely pathogenic 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

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 528248)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.891. BayesDel score = 0.575563.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52676395, n = 181 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.