The TP53 c.1010G>C (p.Arg337Pro) variant has been observed in somatic cancers in COSMIC (6 occurrences) and has been reported in ClinVar as Likely Pathogenic with expert-panel review.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the TP53 VCEP PM2_Supporting threshold.2 In the TP53 VCEP functional worksheet, p.Arg337Pro is listed as non-functional in the Kato dataset and loss-of-function in the Giacomelli framework, supporting a damaging effect on TP53 protein function and PS3.3 Computational evidence is also consistent with a damaging missense effect: the TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C, BayesDel is 0.407328, REVEL is 0.792, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.4
TP53
Final classification
Likely Pathogenic
TP53 c.1010G>C · p.Arg337Pro
TP53
The TP53 c.1010G>C (p.Arg337Pro) variant has been observed in somatic cancers in COSMIC (6 occurrences) and has been reported in ClinVar as Likely Pathogenic with expert-panel review.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 supporting (+1) + PP5 supporting (+1) = 7 points, which maps to Likely Pathogenic.
Classification rationale
PS3PM2PP3PP5
Likely Pathogenic
TP53 c.1010G>C
PS3 + PM2 + PP3 + PP5
→
Likely Pathogenic
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗
4
vcep_pp3_bp4_codesbayesdelrevelspliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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 pathogenic
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 Likely pathogenic (6 clinical laboratories) and as Likely Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.792. BayesDel score = 0.407328.
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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52828545, n = 6 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links