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LYFE SCIENCES
Project: HERA
NM_000546.5:c.743G>T
p.Arg248Leu  ·  TP53
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Classification rationale
1

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.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the TP53 VCEP PM2_Supporting threshold.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:12826609 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.96. BayesDel score = 0.570318.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52675468, n = 161 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueR248
Hotspots ↗