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
TP53
Final classification
Likely Pathogenic
TP53 c.1009C>T · p.Arg337Cys
TP53
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
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
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.
PMID PMID:16007150
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links