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TP53c.1118A>GLikely benign
Print report
Variant interpretation report

TP53 c.1118A>G, p.(Lys373Arg)

NM_000546.6:c.1118A>G NP_000537.3:p.(Lys373Arg) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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.

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. 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

The variant is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting (allele frequency <0.003%).

Benign criteria applied · 2
BS3Strong
BS3 · strong

p.Lys373Arg is functional in the Kato assay (TP53 VCEP Functional-worksheet: 'Functional') with no loss of function by available eligible assays (Giacomelli 'noLOF'); Kim et al. 2012 directly tested K373R and observed wild-type-like transactivation (60-80% of wild type). This meets BS3 (Strong).

BP4Moderate
BP4 · moderate

BP4_Moderate: BayesDel -0.107 (<= -0.008, Class C0) with no predicted splicing impact (SpliceAI max delta 0.04) meets the TP53 VCEP BP4_moderate rule.

Recorded classification: Likely benign

Applied the ClinGen TP53 Expert Panel (VCEP) v2.4 point-based classification framework (Tavtigian Bayesian points system). Adjudicated criteria applied at their assigned strengths: PM2 at supporting (+1 point), BS3 at strong (-4 points), BP4 at moderate (-2 points). Total point value = +1 - 4 - 2 = -5, which falls within the Likely Benign range (>= -6 and <= -2 points, Rule4) of the TP53 VCEP point rules.

02The sources

Evidence at a glance

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

SpliceAI score
0.041 maximum delta

Recorded SpliceAI maximum delta score: 0.041. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions

3 Uncertain significance · 2 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only 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.

Applied · BS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52830683, n = 1 times).

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, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 14 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

TP53 c.1118A>G (p.Lys373Arg) is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting.

Functional evidence shows p.Lys373Arg retains p53 transactivation activity: the TP53 VCEP Functional-worksheet assigns Kato class 'Functional' with no loss of function across available eligible assays (BS3), and Kim et al. 2012 (PMID 22178617) directly observed wild-type-like (60-80%) transactivation for K373R.

Computational evidence supports a benign effect: BayesDel -0.107 (Class C0) and SpliceAI max delta 0.04, meeting BP4_Moderate per the TP53 VCEP.

ClinVar reports this variant as Uncertain significance (3 laboratories) and Likely benign (2 laboratories) with no expert-panel review, consistent with the functional and computational evidence.

Met · 3

PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting (allele frequency <0.003%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exome).
  • Absent from gnomAD v4.1 (exome).
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Strongp.Lys373Arg is functional in the Kato assay (TP53 VCEP Functional-worksheet: 'Functional') with no loss of function by available eligible assays (Giacomelli 'noLOF'); Kim et al. 2012 directly tested K373R and observed wild-type-like transactivation (60-80% of wild type). This meets BS3 (Strong). Details ▾Hide ▴
Evidence considered
  • VCEP Functional-worksheet: K373R -> Kato 'Functional'
  • Giacomelli 'noLOF'
  • preliminary code BS3.
  • PMID 22178617: K373R activated transcription as efficiently as wild-type p53
  • 60-80% of wild-type transactivation in H1299 reporter assays.
Sources
vcep_functional_worksheetPMID:22178617 ↗
BP4 ModerateBP4_Moderate: BayesDel -0.107 (<= -0.008, Class C0) with no predicted splicing impact (SpliceAI max delta 0.04) meets the TP53 VCEP BP4_moderate rule. Details ▾Hide ▴
Evidence considered
  • VCEP PP3-BP4-codes: c.1118A>G -> p.Lys373Arg
  • Class C0
  • BayesDel -0.106697
  • code BP4_moderate.
  • SpliceAI max delta 0.041 (<0.2): no predicted splice alteration.
Sources
vcep_pp3_bp4_codesbayesdelspliceai ↗

Not met · 14 · evaluated, threshold not reached

PS1 No alternative nucleotide change producing the same p.Lys373Arg substitution has been reported as pathogenic/likely pathogenic in ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 577458 reports this exact change as VUS/Likely benign
  • not pathogenic.
  • No same-amino-acid pathogenic comparator identified.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation of this variant (with confirmed parentage) has been reported. Details ▾Hide ▴
Still missing
  • No de novo case data available.
PS3 Functional data indicate p.Lys373Arg retains p53 transactivation activity (Kato class 'Functional' per the VCEP Functional-worksheet; Kim et al. 2012 observed 60-80% of wild-type activity), which is evidence of retained function rather than loss of function, so PS3 is not met. Details ▾Hide ▴
Evidence considered
  • VCEP Functional-worksheet: K373R -> Kato 'Functional'
  • Giacomelli 'noLOF'
  • preliminary code BS3 (not PS3).
  • PMID 22178617: K373R retained wild-type-like transactivation in transcription and luciferase reporter assays.
Sources
vcep_functional_worksheetPMID:22178617 ↗
PS4 No proband phenotype or case-control data are available to tally Li-Fraumeni syndrome cancer points. Details ▾Hide ▴
Still missing
  • No proband phenotype or case-control data.
PM1 p.Lys373Arg lies in the C-terminal regulatory domain, outside the TP53 VCEP PM1 hotspot codons (175, 245, 248, 249, 273, 282); cancerhotspots.org does not flag this residue as significant (COSMIC n=1), so PM1 is not met. Details ▾Hide ▴
Evidence considered
  • VCEP PM1 rule limited to codons 175/245/248/249/273/282 or cancerhotspots.org >=2 somatic occurrences.
  • Residue 373 is not a significant cancerhotspot
  • COSMIC COSV52830683 n=1.
Sources
cspec ↗oncokb ↗
PM5 No pathogenic/likely pathogenic missense variant at codon 373 was identified as a comparator (PM5 candidate search returned zero candidates). Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvesting found zero same-residue pathogenic comparator variants in ClinVar.
Sources
pm5_candidatesclinvar ↗
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No segregation data.
PP3 Computational evidence does not support a deleterious effect: BayesDel -0.107 (Class C0), REVEL 0.407, SpliceAI max delta 0.04; the TP53 VCEP PP3-BP4-codes table assigns 'BP4_moderate' rather than PP3. Details ▾Hide ▴
Evidence considered
  • VCEP PP3-BP4-codes: c.1118A>G -> BayesDel Class C0
  • code BP4_moderate (not PP3).
  • BayesDel -0.106697
  • REVEL 0.407
  • SpliceAI max delta 0.041.
Sources
vcep_pp3_bp4_codesbayesdelrevelspliceai ↗
PP4 No observation of the variant with variant allele fraction 5-35% is available to meet PP4. Details ▾Hide ▴
Still missing
  • No VAF data available.
BA1 The variant is absent from gnomAD, far below the BA1 stand-alone benign threshold (FAF >=0.1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD, below the BS1 strong benign threshold (FAF >=0.03%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data on unrelated females who reached 60 years of age without cancer are available. Details ▾Hide ▴
Still missing
  • No unaffected elderly female observations.
BS4 No segregation data indicating lack of segregation in affected family members are available. Details ▾Hide ▴
Still missing
  • No segregation data.
PS5 PS5 (same nucleotide change previously established as pathogenic) is not part of the TP53 VCEP criteria and no such evidence exists; ClinVar reports this variant as VUS/Likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 577458: VUS (3 labs) and Likely benign (2 labs)
  • no pathogenic assertion.
Sources
clinvar ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Lys373Arg), not a null variant (nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or exon deletion), so PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense substitution p.Lys373Arg in exon 11
  • not a predicted null variant
  • SpliceAI max delta 0.04 (no splice alteration).
Sources
pvs1_gene_contextpvs1_variant_assessment
PM3 VCEPRecessive-disorder criterion; TP53/Li-Fraumeni syndrome is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPProtein-length change (in-frame indel/stop-loss); this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 (assumed de novo without confirmed parentage) is not applicable under the TP53 VCEP, which uses a combined PS2/PM6 de novo rule. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 (missense variant in a gene with a low rate of benign missense variation) is not applicable under the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPPP5 is not for use under the TP53 VCEP; the ClinVar review status is 'criteria provided, single submitter' with no 3-star expert-panel pathogenic classification. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 577458: no expert panel review
  • classification VUS/Likely benign.
Sources
clinvar ↗
BP1 VCEPBP1 (missense variant in a gene where primarily truncating variants cause disease) is not applicable under the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 (observation in trans/cis with a pathogenic variant) is not applicable under the TP53 VCEP, and no such data are available. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPIn-frame deletion/insertion in a repetitive region; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP5 VCEPBP5 (variant found in a case with an alternate molecular basis for disease) is not applicable under the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is not for use under the TP53 VCEP, and there is no 3-star expert-panel benign classification in ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 577458: review status 'criteria provided
  • single submitter'
  • no expert panel.
Sources
clinvar ↗
BP7 N/ABP7 applies to synonymous (silent) variants; this is a missense variant (p.Lys373Arg). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.1118A>G
Protein (HGVS p.)
NP_000537.3:p.(Lys373Arg)
GRCh38
chr17:7669673 T>C
GRCh37
chr17:7572991 T>C
ClinVar
577458
COSMIC
COSV52830683

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +111 bp
0.010
SpliceAI acceptor gainat +17 bp
0.020
SpliceAI donor lossat -2 bp
0.041
SpliceAI donor gainat -163 bp
0.000
Pangolin splice lossmagnitude shown
-0.070
Pangolin splice gain
0.002

Other predictors

REVEL
0.407
BayesDel
-0.107

How the predictions were used

BP4 ModerateBP4_Moderate: BayesDel -0.107 (<= -0.008, Class C0) with no predicted splicing impact (SpliceAI max delta 0.04) meets the TP53 VCEP BP4_moderate rule. Details ▾Hide ▴
Evidence considered
  • VCEP PP3-BP4-codes: c.1118A>G -> p.Lys373Arg
  • Class C0
  • BayesDel -0.106697
  • code BP4_moderate.
  • SpliceAI max delta 0.041 (<0.2): no predicted splice alteration.
Sources
vcep_pp3_bp4_codesbayesdelspliceai ↗
PP3 Computational evidence does not support a deleterious effect: BayesDel -0.107 (Class C0), REVEL 0.407, SpliceAI max delta 0.04; the TP53 VCEP PP3-BP4-codes table assigns 'BP4_moderate' rather than PP3. Details ▾Hide ▴
Evidence considered
  • VCEP PP3-BP4-codes: c.1118A>G -> BayesDel Class C0
  • code BP4_moderate (not PP3).
  • BayesDel -0.106697
  • REVEL 0.407
  • SpliceAI max delta 0.041.
Sources
vcep_pp3_bp4_codesbayesdelrevelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants; this is a missense variant (p.Lys373Arg). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.407. BayesDel score = -0.106697.

9 paper records listed. 1 cited in the classification.

Cited in the classification

  • p53 requires an intact C-terminal domain for DNA binding and transactivation.
    Kim H et al. · 2012 Feb 3
    K373R was among four C-terminal lysine point mutants (K320R, K373R, K381R, K382R) directly assayed. K373R activated p53-dependent transcription from both DNA and chromatin templates as efficiently as wild-type p53 and showed 60-80% of wild-type transactivation in H1299 luciferase reporter assays, indicating retention of p53 function.
    → BS3 Names this variant
    PMID 22178617 ↗
    Source detail
    p53 mutants K373R and K381R were able to activate DNA transcription as efficiently as the wild type protein

    Location Results; Figure 1e; Figure 2

    Context In vitro transcription (DNA and chromatin templates) and H1299 luciferase reporter assays; bacterially expressed Flag-tagged p53

Other recorded publications

  • The role of p53 deacetylation in p21Waf1 regulation by laminar flow.
    Zeng L et al. · 2003
    Reports laminar-flow-induced deacetylation of p53 at Lys-320 and Lys-373 in endothelial cells; discusses the K373 residue but does not report the K373R missense variant.
    Does not name this variant
    PMID 12716906 ↗
  • Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
    Kato S et al. · 2003
    High-resolution missense mutation analysis of p53 structure-function relationships; the full text does not name K373R individually. The TP53 VCEP Functional-worksheet tabulates the Kato assay result for K373R as 'Functional'.
    Does not name this variant
    PMID 12826609 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    ACMG/AMP standards and guidelines for the interpretation of sequence variants; contains no variant-specific content.
    Does not name this variant
    PMID 25741868 ↗
  • G9a stimulates CRC growth by inducing p53 Lys373 dimethylation-dependent activation of Plk1.
    Zhang J et al. · 2018
    G9a-mediated p53 Lys373 dimethylation regulates Plk1 expression in colorectal cancer; discusses the K373 residue as a post-translational modification site but does not report the K373R missense variant.
    Does not name this variant
    PMID 29774081 ↗
  • A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
    Kotler E et al. · 2018
    Systematic library of approximately 10,000 DNA-binding domain (DBD) p53 variants; p.Lys373Arg lies in the C-terminal regulatory domain and is not covered by the DBD library. K373R was not identified in the full text.
    Does not name this variant
    PMID 29979965 ↗
  • Mutational processes shape the landscape of TP53 mutations in human cancer.
    Giacomelli AO et al. · 2018
    Systematic loss-of-function screens across TP53 mutations in human cancer; the abstract does not name K373R. The TP53 VCEP Functional-worksheet tabulates the Giacomelli result for K373R as 'noLOF'.
    Does not name this variant
    PMID 30224644 ↗
  • Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.
    Fayer S et al. · 2021
    Systematic integration of multiplexed functional data to resolve variants of uncertain significance in BRCA1, TP53, and PTEN; the abstract does not name K373R.
    Does not name this variant
    PMID 34793697 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Sherloc refinement of the ACMG-AMP variant classification criteria; background review with no variant-specific content.
    Does not name this variant
    PMID 28492532 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.041 Open source ↗
ClinVar 3 Uncertain significance · 2 Likely benign · 1 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 577458)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.407. BayesDel score = -0.106697.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52830683, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.