TP53c.1136G>TUncertain significance

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Variant interpretation report

TP53 c.1136G>T, p.(Arg379Leu)

NM_000546.5:c.1136G>T NP_000537.3:p.(Arg379Leu) 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 moderate (benign) · 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1, with total AF 1.85874e-06, which is below the TP53 PM2 threshold of 0.00003. Although 2 alleles were observed in the Remaining group, that group frequency was 3.19969e-05, which is below the multiple-allele threshold of 0.00004.
BP4 (moderate): Computational evidence supports a benign effect under the TP53 VCEP rule set. The TP53 in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, and SpliceAI predicts no significant splice impact with max delta score 0.10, which is below the no-splice-impact threshold of 0.2. REVEL was 0.345 and does not override the TP53 VCEP-specific assignment.
BP6 (supporting): Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.

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: 1 Benign evidence criteria: 2

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1, with total AF 1.85874e-06, which is below the TP53 PM2 threshold of 0.00003. Although 2 alleles were observed in the Remaining group, that group frequency was 3.19969e-05, which is below the multiple-allele threshold of 0.00004.

Benign criteria applied · 2

BP4Moderate

BP4 · moderate

Computational evidence supports a benign effect under the TP53 VCEP rule set. The TP53 in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, and SpliceAI predicts no significant splice impact with max delta score 0.10, which is below the no-splice-impact threshold of 0.2. REVEL was 0.345 and does not override the TP53 VCEP-specific assignment.

BP6Supporting

BP6 · supporting

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.

Recorded classification: Uncertain significance

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 moderate (-2) = -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

3 / 1,614,000 alleles

gnomAD v4.1: 3 / 1,614,000 alleles. Recorded AF 1.85874e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Applied · BP6 → ClinVar ↗

Functional evidence

Statement recorded

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.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie 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.

28 criteria with recorded statuses: 3 met · 6 not met · 8 not assessed · 11 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

Benign

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

Met Not met Not assessed Not applicable

The TP53 c.1136G>T (p.Arg379Leu) variant has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign, although additional clinical laboratory submissions are uncertain.

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (3/1614000 alleles; AF 1.85874e-06), supporting PM2_Supporting and arguing against BS1 or BA1.

In the TP53 VCEP functional worksheet, p.Arg379Leu is recorded as partially functional in Kato-class data and noLOF in Giacomelli-class data, with a preassigned interpretation of no functional evidence, so PS3 and BS3 are not supported.

TP53-specific in silico assessment lists c.1136G>T as Class C0 with BayesDel -0.0781755 and BP4_moderate, SpliceAI predicts no significant splice impact with max delta score 0.10, and the available REVEL score is 0.345; together these data support BP4_Moderate rather than PP3.

Met · 3

PM2 SupportingThis variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1, with total AF 1.85874e-06, which is below the TP53 PM2 threshold of 0.00003. Although 2 alleles were observed in the Remaining group, that group frequency was 3.19969e-05, which is below the multiple-allele threshold of 0.00004. Details ▾Hide ▴

Rule

TP53 VCEP PM2_Supporting: allele frequency <0.00003 overall; if multiple alleles are present within any ancestry group, frequency must be <0.00004.

Evidence considered

gnomAD v2.1: absent.
gnomAD v4.1: 3/1614000 alleles
total AF 1.858736059479554e-06
homozygotes 0.
Highest observed subpopulation frequency: Remaining 2/62506
AF 3.1996928294883694e-05.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 ModerateComputational evidence supports a benign effect under the TP53 VCEP rule set. The TP53 in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, and SpliceAI predicts no significant splice impact with max delta score 0.10, which is below the no-splice-impact threshold of 0.2. REVEL was 0.345 and does not override the TP53 VCEP-specific assignment. Details ▾Hide ▴

Rule

TP53 VCEP BP4_Moderate for missense variants: BayesDel <= -0.008 and no predicted differences in splicing (SpliceAI < 0.2).

Evidence considered

PP3-BP4 worksheet row: c.1136G>T / p.Arg379Leu / Class C0 / BayesDel -0.0781755 / BP4_moderate / SpliceAI 0.1.
SpliceAI max delta score: 0.10.
REVEL score: 0.345.

Sources

cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

BP6 SupportingExpert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP6 as not applicable.
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 6 · evaluated, threshold not reached

PS3 Available TP53 functional evidence does not show the level of loss of function required for PS3. In the TP53 functional worksheet, p.Arg379Leu is listed as partially functional in Kato-class data and noLOF in Giacomelli-class data, with a preassigned interpretation of no functional evidence for PS3/BS3. Details ▾Hide ▴

Evidence considered

Functional worksheet row: R379L / Partially functional / noLOF / Preliminary functional code: No evidence.

Sources

cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗

PM1 Available hotspot evidence does not support PM1. This variant is outside the TP53 codons predefined for PM1, and no statistically significant hotspot evidence was identified for p.Arg379Leu. Details ▾Hide ▴

Evidence considered

TP53 VCEP predefined PM1 codons are 175
245
248
249
273
and 282.
Cancer Hotspots summary states that this variant does not lie in a statistically significant hotspot.

Sources

cspec ↗hotspots ↗

PP3 Available computational evidence does not meet the TP53 PP3 thresholds. The TP53 VCEP in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, while SpliceAI predicts no significant splice effect with max delta score 0.10. REVEL was 0.345, but the TP53 VCEP-specific in silico rule set does not support PP3 for this variant. Details ▾Hide ▴

Evidence considered

PP3-BP4 worksheet row: c.1136G>T / p.Arg379Leu / Class C0 / BayesDel -0.0781755 / BP4_moderate / SpliceAI 0.1.
REVEL score: 0.345.

Sources

cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

BA1 Population frequency does not meet the TP53 BA1 threshold. The highest observed subpopulation frequency was 3.19969e-05, which is below the BA1 cutoff of 0.001. Details ▾Hide ▴

Evidence considered

Highest observed subpopulation frequency: Remaining 2/62506
AF 3.1996928294883694e-05.

Sources

cspec ↗gnomad_v4 ↗

BS1 Population frequency does not meet the TP53 BS1 threshold. The highest observed subpopulation frequency was 3.19969e-05, which is below the BS1 cutoff of 0.0003. Details ▾Hide ▴

Evidence considered

Highest observed subpopulation frequency: Remaining 2/62506
AF 3.1996928294883694e-05.

Sources

cspec ↗gnomad_v4 ↗

BS3 Available TP53 functional evidence does not support BS3. In the TP53 functional worksheet, p.Arg379Leu is listed as partially functional in Kato-class data and noLOF in Giacomelli-class data, but the preassigned interpretation is no functional evidence rather than BS3 or BS3_Supporting. Details ▾Hide ▴

Evidence considered

Functional worksheet row: R379L / Partially functional / noLOF / Preliminary functional code: No evidence.

Sources

cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗

Not assessed · 8 · no assessment recorded

PS1 No reviewed evidence was identified showing that another nucleotide change causing the same TP53 p.Arg379Leu amino acid substitution has already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

ClinVar contains this exact variant
but no same-amino-acid alternate nucleotide comparison was documented in the reviewed files.

Still missing

A same-amino-acid pathogenic comparison variant was not documented in the reviewed evidence.

Sources

cspec ↗clinvar ↗

PS2 No confirmed de novo occurrence data with parental confirmation were identified, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴

Evidence considered

Exploratory review did not identify confirmed de novo observations for this variant.

Still missing

No informative de novo case data were identified.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

PS4 No proband-count or case-enrichment evidence was identified that would allow scoring this variant under the TP53 PS4 point system. Details ▾Hide ▴

Evidence considered

ClinVar presence alone does not provide the TP53 VCEP PS4 point total required for code application.

Still missing

No variant-specific affected proband counts or Li-Fraumeni syndrome point totals were identified.

Sources

cspec ↗vcep_ps4_points_tableclinvar ↗

PM5 No reviewed evidence was identified showing that other missense variants at codon 379 have already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework, so PM5 could not be assessed from the available materials. Details ▾Hide ▴

Evidence considered

The reviewed materials did not document qualifying TP53 VCEP pathogenic missense variants at Arg379.

Still missing

Residue-specific TP53 VCEP pathogenic comparison variants were not documented in the reviewed files.

Sources

cspec ↗clinvar ↗

PP1 No segregation data were identified to show cosegregation with Li-Fraumeni syndrome-associated cancers, so PP1 cannot be assessed. Details ▾Hide ▴

Evidence considered

Exploratory review did not identify variant-specific segregation evidence.

Still missing

No informative meioses or family segregation data were identified.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

PP4 No phenotype-specific evidence, blood variant allele fraction data, or repeated low-level observations were identified to support TP53 PP4. Details ▾Hide ▴

Evidence considered

Reviewed materials did not contain TP53 PP4-supporting clinical observation data.

Still missing

No qualifying phenotype/VAF observations were identified.

Sources

cspec ↗

BS2 No single-source dataset of unaffected older female carriers was identified, so BS2 cannot be assessed. Details ▾Hide ▴

Evidence considered

Reviewed materials did not contain BS2-style unaffected carrier counts.

Still missing

No qualifying unaffected carrier series were identified.

Sources

cspec ↗

BS4 No nonsegregation data were identified in affected relatives with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be assessed. Details ▾Hide ▴

Evidence considered

Reviewed materials did not contain BS4-supporting family data.

Still missing

No informative nonsegregation data were identified.

Sources

cspec ↗

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant, and available TP53-specific PVS1 review indicates it does not fall into the null-variant or canonical splice categories used for PVS1. No RNA evidence was identified to show a loss-of-function splicing effect. Details ▾Hide ▴

Evidence considered

TP53 is PVS1-eligible at the gene level under the TP53 VCEP framework.
c.1136G>T is not a nonsense
frameshift
or canonical +/-1
2 splice variant.
Variant-level PVS1 assessment states that the variant does not fall into the default generic PVS1 null-variant buckets.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_flowchart

PM3 N/APM3 is not applicable in the TP53 VCEP framework for this condition. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PM3 as not applicable.

Sources

cspec ↗

PM4 N/APM4 is not applicable because this variant is a missense substitution, not a protein length-changing in-frame insertion/deletion or stop-loss variant. Details ▾Hide ▴

Evidence considered

Protein consequence is p.Arg379Leu missense.

Sources

cspec ↗

PM6 N/APM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PM6 as not applicable.

Sources

cspec ↗

PP2 N/APP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PP2 as not applicable.

Sources

cspec ↗

PP5 N/APP5 is not for use in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PP5 as not applicable.

Sources

cspec ↗

BP1 N/ABP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP1 as not applicable.

Sources

cspec ↗

BP2 N/ABP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP2 as not applicable.

Sources

cspec ↗

BP3 N/ABP3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP3 as not applicable.

Sources

cspec ↗

BP5 N/ABP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP5 as not applicable.

Sources

cspec ↗

BP7 N/ABP7 is not applicable because this is not a synonymous or qualifying intronic variant. Details ▾Hide ▴

Evidence considered

Protein consequence is missense p.Arg379Leu.

Sources

cspec ↗spliceai ↗

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.1136G>T
Protein (HGVS p.): NP_000537.3:p.(Arg379Leu)
GRCh38: chr17:7669655 C>A
GRCh37: chr17:7572973 C>A

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

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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 3 / 1,614,000 alleles AF 1.86e-06 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,000 alleles · 0 hom

Remaining individuals2 / 62,506	3.2e-05
East Asian1 / 44,876	2.2e-05

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

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85874e-06; MAF= 0.00019%, 3/1614000 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.19969e-05; MAF= 0.00320%, 2/62506 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

TP53 VCEP BP4_Moderate for missense variants: BayesDel <= -0.008 and no predicted differences in splicing (SpliceAI < 0.2).

Evidence considered

PP3-BP4 worksheet row: c.1136G>T / p.Arg379Leu / Class C0 / BayesDel -0.0781755 / BP4_moderate / SpliceAI 0.1.
SpliceAI max delta score: 0.10.
REVEL score: 0.345.

Sources

cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

Evidence considered

PP3-BP4 worksheet row: c.1136G>T / p.Arg379Leu / Class C0 / BayesDel -0.0781755 / BP4_moderate / SpliceAI 0.1.
REVEL score: 0.345.

Sources

cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

BP7 N/ABP7 is not applicable because this is not a synonymous or qualifying intronic variant. Details ▾Hide ▴

Evidence considered

Protein consequence is missense p.Arg379Leu.

Sources

cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.345. BayesDel score = -0.0781755.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 3 / 1,614,000 recorded alleles Open source ↗

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

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record 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 (7 clinical laboratories) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.345. BayesDel score = -0.0781755.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.