The TP53 c.743G>T (p.Arg248Leu) variant has been observed in somatic cancers in COSMIC 161 times and has been reported in ClinVar with an expert panel pathogenic classification.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the TP53 VCEP PM2_Supporting threshold.2 In the TP53 VCEP functional worksheet, p.Arg248Leu is summarized as non-functional with loss-of-function results across eligible assays and is pre-assigned PS3, supporting a damaging effect on p53 function.3 In the TP53 VCEP bioinformatic worksheet, this missense change is pre-assigned PP3_moderate with Align-GVGD class C65 and BayesDel 0.570318, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.01; REVEL is also high at 0.96.4
Final classification
Pathogenic
PS3PM1PM2PP3PP5
TP53
c.743G>T
p.Arg248Leu
This variant
The TP53 c.743G>T (p.Arg248Leu) variant has been observed in somatic cancers in COSMIC 161 times and has been reported in ClinVar with an expert panel pathogenic classification.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM1 moderate (+2) + PM2 supporting (+1) + PP3 moderate (+2) + PP5 supporting (+1) = 10 points, which maps to Pathogenic.
Classification rationale
PS3PM1PM2PP3PP5
Pathogenic
TP53 c.743G>T
PS3 + PM1 + PM2 + PP3 + PP5
→
Pathogenic
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗
4
vcep_pp3_bp4_codesbayesdelspliceai ↗revel
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may be applied incorrectly, sources may be misread, and a confident-looking
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Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 12 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In the TP53 functional worksheet, p.Arg248Leu is pre-assigned PS3. The compiled eligible assay results show this variant was non-functional in the Kato transactivation dataset and showed loss of function in the other eligible functional assays summarized for TP53, supporting a damaging effect on protein function.
Functional worksheet row: R248L -> Non-functional / LOF / LOF / LOF -> PS3TP53 VCEP functional flowchart for PS3/BS3 interpretation
PM1
moderate
Pathogenic
This missense variant affects TP53 codon 248, one of the codons explicitly specified by the TP53 VCEP for PM1 at moderate strength. The same amino acid change has also been observed 161 times in COSMIC, consistent with recurrence at this hotspot residue.
TP53 VCEP PM1 codon list includes codon 248COSMIC somatic count 161 for this amino acid change
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the ancestry-group threshold of less than 0.00004 when multiple alleles are present.
Absent from gnomAD v2.1Absent from gnomAD v4.1TP53 VCEP PM2 threshold
PP3
moderate
Pathogenic
In the TP53 VCEP bioinformatic worksheet, NM_000546.5:c.743G>T (p.Arg248Leu) is pre-assigned PP3_moderate. The entry shows Align-GVGD class C65 and BayesDel 0.570318, which is above the TP53 VCEP PP3_Moderate threshold of 0.16, and SpliceAI predicts no meaningful splice effect (max delta score 0.01). REVEL is also high at 0.96, which is consistent with a damaging missense effect.
PP3-BP4 worksheet row: c.743G>T p.Arg248Leu -> Class C65BayesDel 0.570318PP3_moderate
Assessed · not applied
· 4 not met · 8 not assessed
Pathogenic
PS1
No alternate nucleotide change producing the same TP53 p.Arg248Leu amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic assertion was identified in the reviewed evidence.
PS2
No confirmed de novo observation with maternity and paternity assessment and the phenotype details required for TP53 point-based scoring was identified.
PS4
This variant meets PM2_Supporting as a population prerequisite for TP53 PS4, but no germline proband-level Li-Fraumeni syndrome cancer observations with enough information to assign TP53 PS4 points were identified.
PM5
The reviewed evidence confirms that this variant affects codon 248, but it does not document the number of different TP53 VCEP-classified pathogenic or likely pathogenic missense variants already established at this same residue for direct PM5 scoring.
PP1
No segregation data with informative meioses across one or more families were identified for this variant.
PP4
No blood variant allele fraction data or phenotype observations meeting the TP53 VCEP PP4 low-level mosaicism framework were identified.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BA1 threshold of filtering allele frequency at or above 0.001.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BS1 threshold of filtering allele frequency at or above 0.0003 and below 0.001.
BS2
No single-source dataset showing unrelated females age 60 years or older without cancer who carry this variant was identified.
BS3
Available functional evidence does not support retained or near-normal TP53 function.
BS4
No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified.
BP4
Available computational evidence does not support a benign missense effect.
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 (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as 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 = 0.01). REVEL score = 0.96. BayesDel score = 0.570318.
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; COSV52675468, n = 161 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