The TP53 c.344A>G (p.His115Arg) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 and supports rarity in population databases.2 In TP53 functional studies summarized by the TP53 VCEP functional worksheet, p.His115Arg was functional in Kato data and showed no loss of function in Giacomelli and Kotler data, supporting BS3.3 TP53-specific in silico assessment assigns BP4 because BayesDel is 0.0464313, below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03 below the 0.2 threshold; REVEL is 0.484.4
Final classification
Likely Benign
PM2BS3BP4BP6
TP53
c.344A>G
p.His115Arg
This variant
The TP53 c.344A>G (p.His115Arg) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign.
TP53 VCEP v2.4.0 Tavtigian point framework: BS3_Strong (-4) + BP4_Supporting (-1) + PM2_Supporting (+1) = -4 points.
Classification rationale
PM2
BS3BP4BP6
Likely Benign
TP53 c.344A>G
PM2 + BS3 + BP4 + BP6
→
Likely Benign
3
vcep_functional_worksheetPMID:12826609 ↗PMID:29979965 ↗
4
vcep_pp3_bp4_codesbayesdelspliceai ↗revel
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.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall allele frequency and supports rarity in population databases.
Absent from gnomAD v2.1Absent from gnomAD v4.1
BS3
strong
Benign
Published TP53 functional evidence supports normal or near-normal protein function rather than loss of function. In the TP53 functional worksheet, p.His115Arg is listed as Functional in Kato data and noLOF in both Giacomelli and Kotler data, and the pre-assigned TP53 VCEP functional code is BS3.
Functional worksheet row for H115R: Functional in KatonoLOF in GiacomellinoLOF in Kotler
BP4
supporting
Benign
Available computational evidence supports a benign interpretation under TP53 VCEP rules. The TP53 PP3/BP4 worksheet assigns BP4 for c.344A>G, BayesDel is 0.0464313 which is below the TP53 PP3 threshold of 0.16 and within the BP4-supporting range, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.03 below the 0.2 threshold. REVEL is 0.484 and does not override the TP53 VCEP-specific BP4 assignment.
PP3/BP4 worksheet row for c.344A>G assigns BP4BayesDel 0.0464313SpliceAI max delta 0.03
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No reviewed evidence identified an established TP53 VCEP Pathogenic or Likely Pathogenic variant that creates the same amino acid change, so PS1 was not assessed.
PS2
No confirmed de novo observations with appropriate parental confirmation were identified, so PS2 was not assessed.
PS3
Available TP53 functional evidence does not support a damaging effect sufficient for PS3.
PS4
No proband-based Li-Fraumeni syndrome point total was identified for this variant, so PS4 was not assessed.
PM1
This missense change is not at one of the TP53 codons predefined for PM1 application, and reviewed hotspot evidence did not show a statistically significant somatic hotspot or recurrent exact amino acid change count sufficient for TP53 PM1.
PM5
TP53 uses classic same-residue missense PM5 logic, but no validated previously classified pathogenic or likely pathogenic same-residue comparator was established from the reviewed materials, so PM5 was not assessed.
PP1
No segregation data were identified to show cosegregation with Li-Fraumeni syndrome-associated cancers, so PP1 was not assessed.
PP3
Available computational evidence does not support a damaging prediction under TP53 VCEP rules.
PP4
No low-variant-allele-fraction constitutional mosaicism evidence or other qualifying TP53-specific phenotype data were identified, so PP4 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BA1 threshold of filtering allele frequency at or above 0.001.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BS1 threshold of filtering allele frequency at or above 0.0003.
BS2
No single-source series of unaffected females age 60 years or older carrying this variant was identified, so BS2 was not assessed.
BS4
No lack-of-segregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not assessed.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 182925)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.484. BayesDel score = 0.0464313.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
8023157 ↗
Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.
ONCOKB
11313981 ↗
p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay.
CLINVAR
25741868 ↗
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.
CLINVAR
28861920 ↗
Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR