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LYFE SCIENCES
Project: HERA
NM_000546.5:c.1031T>C
p.Leu344Pro  ·  TP53
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Classification rationale
1

The TP53 c.1031T>C (p.Leu344Pro; p.L344P) variant has been observed in somatic cancer curation resources and has been reported in ClinVar, including a ClinGen TP53 Variant Curation Expert Panel likely pathogenic assertion.

oncokb ↗ clinvar ↗
2

This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07), with the highest observed population frequency in South Asian individuals of 1/91074 (AF 1.0980e-05), supporting rarity for TP53.

gnomad_v2 ↗ gnomad_v4 ↗
3

In TP53 functional studies summarized by the TP53 VCEP, p.Leu344Pro showed non-functional activity, loss-of-function behavior across eligible assays, and monomeric oligomerization-domain behavior, supporting a damaging loss-of-function effect.

PMID:12826609 ↗ PMID:9704930 ↗ PMID:19106109 ↗ PMID:19454241 ↗ PMID:20978130 ↗
4

Computational evidence is concordant with a damaging missense effect, with a TP53 VCEP pre-assigned PP3_moderate call, BayesDel 0.485604, and REVEL 0.862.

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
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Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.1955e-07; MAF= 0.00006%, 1/1614076 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09801e-05; MAF= 0.00110%, 1/91074 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely 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: 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 = 0.00). REVEL score = 0.862. BayesDel score = 0.485604.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52687285, n = 11 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueL344
Hotspots ↗