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
TP53
Final classification
Pathogenic
TP53 c.743G>T · p.Arg248Leu
TP53
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
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 5 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
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.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links