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LYFE SCIENCES
Project: HERA
NM_000546.5:c.215C>G
p.Pro72Arg  ·  TP53
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Classification rationale
1

The TP53 c.215C>G (p.Pro72Arg, p.P72R) variant has not been observed in COSMIC as a recurrent somatic cancer variant and is reported in ClinVar as benign, including a benign ClinGen TP53 Variant Curation Expert Panel classification.

clinvar ↗
2

This variant is very common in population databases, with gnomAD v4.1 total allele frequency 0.707882 and grpmax filtering allele frequency 0.746273, far above the TP53 BA1 benign threshold of 0.001.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Available studies of the common TP53 codon 72 polymorphism describe biologic differences between alleles, but no TP53 VCEP-eligible functional code assignment for p.Pro72Arg was identified in the TP53 functional worksheet.

PMID:10802655 ↗ PMID:12567188 ↗ PMID:16964264 ↗
4

TP53 VCEP in silico data support a benign interpretation because c.215C>G is assigned BP4_moderate in the TP53 PP3/BP4 worksheet with BayesDel -0.108475, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.05.

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
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 0.662887; MAF= 66.28868%, 186832/281846 alleles, homozygotes = 63926) and has highest observed frequency in the European (non-Finnish) population (AF= 0.73659; MAF= 73.65900%, 94889/128822 alleles, homozygotes = 34940); grpmax FAF= 0.733613.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.707882; MAF= 70.78822%, 1142226/1613582 alleles, homozygotes = 411964) and has highest observed frequency in the European (non-Finnish) population (AF= 0.747582; MAF= 74.75821%, 882123/1179968 alleles, homozygotes = 329809); grpmax FAF= 0.746273.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (25 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP72
Hotspots ↗