The TP53 c.1010G>T (p.Arg337Leu; p.R337L) variant has been observed in somatic cancers in COSMIC (COSV52665150, n=69) and has been reported in ClinVar, including a ClinGen TP53 expert panel classification of Likely Pathogenic.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the TP53 PM2_Supporting threshold of less than 0.00003.2 In TP53 functional data summarized by the TP53 VCEP, p.Arg337Leu was non-functional with loss-of-function findings and monomerization, supporting a damaging effect on protein function and meeting PS3.3 In the TP53-specific computational framework, SpliceAI predicts no splice effect (max delta score 0.00) and the TP53 VCEP bioinformatic worksheet assigns BP4 with a BayesDel score of 0.0670081; REVEL was 0.765, but the TP53 precomputed PP3/BP4 assignment supports BP4 rather than PP3 for this variant.4
Final classification
VUS
PS3PM2PP5BP4
TP53
c.1010G>T
p.Arg337Leu
This variant
The TP53 c.1010G>T (p.Arg337Leu; p.R337L) variant has been observed in somatic cancers in COSMIC (COSV52665150, n=69) and has been reported in ClinVar, including a ClinGen TP53 expert panel classification of Likely Pathogenic.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP5 supporting (+1) + BP4 supporting (-1) = 5 points, which maps to VUS.
Classification rationale
PS3PM2PP5
BP4
VUS
TP53 c.1010G>T
PS3 + PM2 + PP5 + BP4
→
VUS
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:16007150 ↗PMID:30224644 ↗
4
spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
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_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
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.Arg337Leu is summarized as non-functional with loss-of-function findings across eligible assays and monomerization, which supports a damaging effect on TP53 protein function. This meets TP53 PS3 at strong strength.
Functional worksheet row: R337L | NA | Non-functional | NA | LOF | NA | Monomer | PS3TP53 VCEP flowchart maps non-functional/LOF assay profiles to PS3
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of less than 0.00003 (0.003%) in a large sequenced population.
Absent from gnomAD v2.1Absent from gnomAD v4.1
BP4
supporting
Benign
The TP53 VCEP bioinformatic worksheet assigns BP4 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the no-splicing-impact threshold of 0.2. These findings support BP4.
PP3-BP4 worksheet row assigns BP4BayesDel score 0.0670081SpliceAI max delta 0.00
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified by the TP53 VCEP at a qualifying pathogenic or likely pathogenic level.
PS2
No confirmed de novo observations with the point-based TP53 evidence required for PS2 were identified.
PS4
Although this variant is rare in population databases, no case-level TP53 point total from affected individuals was identified to support PS4 under the Li-Fraumeni syndrome scoring framework.
PM1
This missense variant is not in one of the TP53 codons pre-specified for PM1, and the available hotspot review did not verify that this exact amino acid change is listed in Cancer Hotspots with the somatic recurrence required for TP53 PM1 application.
PM5
No qualifying same-residue pathogenic or likely pathogenic comparator variant was confirmed from the available reviewed materials, so PM5 was not applied.
PP1
No segregation data were identified to show cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses.
PP3
The TP53 VCEP bioinformatic worksheet assigns BP4 rather than PP3 for this variant.
PP4
No blood variant allele fraction or mosaicism-related clinical observations were identified to support TP53 PP4.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the TP53 BA1 threshold of at least 0.001 (0.1%) in a qualifying population.
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 in a qualifying population.
BS2
No evidence was identified showing this variant in the number of unrelated females age 60 years or older without cancer required for TP53 BS2.
BS3
Available TP53 functional evidence does not show retained function.
BS4
No lack-of-segregation data were identified in affected family members with Li-Fraumeni syndrome-associated cancers.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
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 (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142828)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.765. BayesDel score = 0.0670081.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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; COSV52665150, n = 69 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers 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
The relationship among p53 oligomer formation, structure and transcriptional act
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links