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
Final classification
Likely Pathogenic
PS3PM2PP3PP5
TP53
c.1010G>C
p.Arg337Pro
This variant
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
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
PS3
strong
Pathogenic
In the TP53 VCEP functional worksheet, p.Arg337Pro is listed as non-functional in the Kato transactivation dataset and loss-of-function in the Giacomelli assay framework, with a preliminary TP53 VCEP assignment of PS3, supporting a damaging effect on protein function.
Functional worksheet row: R337P / Kato non-functional / Giacomelli LOF / preliminary code PS3.TP53 VCEP functional flowchart identifies this worksheet as the primary code-assignment source.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall allele frequency and supports PM2 at the supporting level.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.TP53 VCEP specifies PM2 only at supporting strength.
PP3
supporting
Pathogenic
The TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C based on Align-GVGD class C25 and BayesDel score 0.407328. SpliceAI predicts no splice effect with a maximum delta score of 0.00, and REVEL is high at 0.792, which is consistent with a damaging missense prediction.
PP3-BP4 worksheet row: c.1010G>C / p.Arg337Pro / Class C25 / BayesDel 0.407328 / PP3 / SpliceAI 0.REVEL score 0.792.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified showing that a different nucleotide change causing the same p.Arg337Pro amino acid substitution has already been classified by the TP53 VCEP at the strength required for PS1.
PS2
No confirmed de novo occurrence with the phenotype-specific TP53 point framework was identified, so PS2 cannot be applied from the currently reviewed evidence.
PS4
Although this variant has been reported in ClinVar and in somatic cancers, no proband-level Li-Fraumeni syndrome point total was identified from the reviewed evidence, so PS4 cannot be assigned.
PM1
p.Arg337Pro is not in the TP53 codons specified for PM1_Moderate, and the reviewed evidence did not establish exact Cancer Hotspots support required to apply PM1_Supporting for this amino acid change.
PM5
No reviewed source established that one or more different missense variants at codon 337 had already been classified by the TP53 VCEP at the strengths required for PM5.
PP1
No segregation data were identified showing cosegregation of this variant with TP53-associated cancers across the meiosis counts required for PP1.
PP4
No validated low variant-allele-fraction observation in blood or qualifying mosaicism-style evidence was identified, so PP4 cannot be applied from the reviewed evidence.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BA1 threshold of at least 0.001 filtering allele frequency in a qualifying ancestry group.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BS1 threshold of at least 0.0003 filtering allele frequency in a qualifying ancestry group.
BS2
No single-source dataset was identified showing the number of unrelated females aged 60 years or older without cancer required to apply BS2.
BS3
Available functional evidence does not support retained or partially retained TP53 function.
BS4
No family data were identified showing lack of segregation of this variant with TP53-associated cancers, so BS4 cannot be assessed.
BP4
Available computational evidence does not support BP4.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
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.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links