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
TP53
Final classification
Likely Benign
TP53 c.344A>G · p.His115Arg
TP53
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
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID PMID:29979965
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links
Triaged references · 9 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
12826609 ↗
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
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
29979965 ↗
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR