The TP53 c.1009C>T (p.Arg337Cys) variant has been observed in somatic cancer resources and is reported in ClinVar with a Pathogenic expert-panel assertion.1 This variant is absent from gnomAD v2.1 and is not observed in gnomAD v4.1 (0/1613822 alleles), which supports rarity under the TP53 PM2_Supporting threshold.2 In the TP53 VCEP functional framework, published assay evidence compiled in the expert-panel worksheet shows p.Arg337Cys is non-functional or loss-of-function, with a PS3 assignment supporting a damaging effect on p53 activity.3 For in silico evaluation, the TP53 VCEP bioinformatic worksheet assigns PP3 to this missense change; BayesDel is 0.316468, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00).4
Final classification
Likely Pathogenic
PS3PM2PP3PP5
TP53
c.1009C>T
p.Arg337Cys
This variant
The TP53 c.1009C>T (p.Arg337Cys) variant has been observed in somatic cancer resources and is reported in ClinVar with a Pathogenic expert-panel assertion.
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.1009C>T
PS3 + PM2 + PP3 + PP5
→
Likely Pathogenic
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:16007150 ↗
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
review
Pathogenic
In the TP53 VCEP functional worksheet, p.Arg337Cys is assigned PS3. The compiled assay results list the variant as non-functional in Kato, loss-of-function in Giacomelli, and monomer in Kawaguchi, supporting a damaging effect on p53 function.
Functional worksheet row: R337C | NA | Non-functional | NA | LOF | NA | Monomer | PS3.TP53 VCEP functional flowchart designates pre-assigned functional codes from eligible assays.
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and has 0/1,613,822 alleles in gnomAD v4.1, which is below the TP53 PM2 threshold of less than 0.00003 overall and below the single-population threshold of less than 0.00004.
gnomAD v2.1: absent.gnomAD v4.1: total AF 0.0AC 0/1
PP3
supporting
review
Pathogenic
For the TP53 missense-specific in silico framework, the VCEP worksheet assigns PP3 to c.1009C>T (p.Arg337Cys). BayesDel is 0.316468, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00).
PP3-BP4 worksheet row: c.1009C>T | p.Arg337Cys | Class C45 | 0.316468 | PP3 | 0.01.REVEL score 0.715.SpliceAI max delta score 0.00.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No verified evidence was identified showing that a different nucleotide change produces the same amino acid substitution and has already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework.
PS2
No confirmed de novo observation with sufficient clinical point scoring was identified for this variant, so PS2 cannot be applied from the available evidence.
PS4
This variant is rare enough to satisfy the TP53 rarity gate for PS4 evaluation, but no verified proband-based Li-Fraumeni syndrome point total was identified, so PS4 cannot be applied from the current evidence.
PM1
p.Arg337Cys is not one of the TP53 codons with automatic PM1 application, and the available hotspot review did not verify the Cancer Hotspots evidence needed to use the alternative somatic-occurrence PM1 rule.
PM5
No verified same-residue pathogenic or likely pathogenic comparator variant classified under the TP53 VCEP framework was confirmed for codon 337, so PM5 was not applied.
PP1
No segregation data were identified that established cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 cannot be applied.
PP4
No qualifying low-variant-allele-fraction blood observation or other TP53-specific PP4 data were identified, so PP4 cannot be applied.
Benign
BA1
This variant does not meet BA1 because it is absent from gnomAD v2.1 and has an allele frequency of 0.0 in gnomAD v4.1, which is below the TP53 BA1 threshold of at least 0.001.
BS1
This variant does not meet BS1 because it is absent from gnomAD v2.1 and has an allele frequency of 0.0 in gnomAD v4.1, which is below the TP53 BS1 threshold of at least 0.0003.
BS2
No source identified 2 or more unrelated women aged at least 60 years without cancer carrying this variant from a single dataset, so BS2 cannot be applied.
BS3
Available TP53 functional evidence does not support retained or partially retained p53 function.
BS4
No family data were identified showing lack of segregation of this variant with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be applied.
BP4
BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3, not BP4, to p.Arg337Cys.
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
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613822 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74914 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,613,822
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 Pathogenic (5 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142536)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.715. BayesDel score = 0.316468.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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; COSV52669243, n = 168 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.
The relationship among p53 oligomer formation, structure and transcriptional act
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links