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LYFE SCIENCES
Project: HERA
NM_000546.6:c.1010G>T
p.Arg337Leu  ·  TP53
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:12826609 ↗ PMID:16007150 ↗ PMID:30224644 ↗
4

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.

spliceai ↗ cspec ↗
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 Likely Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142828)
ClinVar ↗
03
Functional
No functional summary recorded.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.765. BayesDel score = 0.0670081.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52665150, n = 69 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueR337
Hotspots ↗