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.1 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 0.001.2 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.3 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 0.05.4
Final classification
Benign
BA1BP4
TP53
c.215C>G
p.Pro72Arg
This variant
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.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: BA1 stand-alone benign (-8) + BP4 moderate (-2) = -10 points, which maps to Benign.
Classification rationale
BA1BP4
Benign
TP53 c.215C>G
BA1 + BP4
→
Benign
3
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tPMID:10802655 ↗PMID:12567188 ↗PMID:16964264 ↗
4
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗cspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
BA1
stand-alone
Benign
This variant exceeds the TP53 VCEP BA1 stand-alone benign threshold by a wide margin. In gnomAD v4.1 the highest observed filtering allele frequency is 0.746273 and in gnomAD v2.1 it is 0.733613, whereas BA1 requires a filtering allele frequency of at least 0.001 in a qualifying ancestry group.
gnomAD v4.1 grpmax FAF 0.746273.gnomAD v2.1 grpmax FAF 0.733613.
BP4
moderate
Benign
TP53 VCEP in silico evidence supports a benign interpretation. In the TP53 PP3/BP4 worksheet, c.215C>G is assigned BP4_moderate with BayesDel -0.108475, which is below the BP4_moderate threshold of -0.008, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, which is below the no-splicing-impact threshold of 0.2.
TP53 PP3-BP4 worksheet row for c.215C>G: Class C0BayesDel -0.108475BP4_moderate.
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified in the reviewed sources showing that this nucleotide change creates the same amino acid substitution as a TP53 variant previously classified as pathogenic or likely pathogenic under TP53 VCEP rules.
PS2
No confirmed de novo observations were identified for this variant, so PS2 cannot be applied.
PS3
Available publications describe biologic differences between codon 72 alleles, but no TP53 VCEP-eligible functional assignment showing non-functional or loss-of-function behavior for p.Pro72Arg was identified, so PS3 is not met.
PS4
Available evidence does not show enrichment of this variant in individuals with TP53-related disease.
PM1
This variant is not located in a TP53 mutational hotspot supported by the TP53 VCEP PM1 rules, and no significant hotspot row was identified for p.Pro72Arg.
PM2
Population frequency is far above the TP53 VCEP PM2 threshold.
PM5
No reviewed source established that other missense variants at codon 72 have been previously classified as pathogenic or likely pathogenic under TP53 VCEP rules, so PM5 was not applied.
PP1
No segregation data were identified for this variant, so PP1 cannot be applied.
PP3
TP53 VCEP in silico data do not support a damaging effect.
PP4
No qualifying low-variant-allele-fraction observation was identified, so the TP53-specific PP4 criterion was not applied.
Benign
BS1
Population frequency is far above the BS1 threshold, but BA1 is already met at stand-alone strength, so BS1 was not additionally applied to avoid double counting the same population evidence.
BS2
No single-source series of unaffected older female carriers was identified, so BS2 cannot be applied.
BS3
Available publications describe functional differences between codon 72 alleles, but no TP53 VCEP-eligible functional assignment showing retained function for p.Pro72Arg was identified in the TP53 functional worksheet, so BS3 is not met.
BS4
No family data showing lack of segregation with Li-Fraumeni spectrum cancers were identified, so BS4 cannot be applied.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
71%
· 1142226 / 1,613,582
411964 hom · FAF 75%
411964 hom · FAF 75%
European (non-Finnish) 882123 / 1,179,968 |
75% 329809 hom |
European (Finnish) 46913 / 63,994 |
73% 17252 hom |
Ashkenazi Jewish 21300 / 29,604 |
72% 7644 hom |
Admixed American 42617 / 59,976 |
71% 15147 hom |
Remaining individuals 43349 / 62,476 |
69% 15169 hom |
Amish 611 / 912 |
67% 207 hom |
Middle Eastern 3519 / 5,810 |
61% 1103 hom |
East Asian 26984 / 44,862 |
60% 8137 hom |
South Asian 46205 / 91,050 |
51% 12001 hom |
African/African American 28605 / 74,930 |
38% 5495 hom |
gnomAD v2.1
66%
· 186832 / 281,846
63926 hom · FAF 73%
63926 hom · FAF 73%
European (non-Finnish) 94889 / 128,822 |
74% 34940 hom |
European (Finnish) 18300 / 25,100 |
73% 6645 hom |
Ashkenazi Jewish 7414 / 10,366 |
72% 2641 hom |
Admixed American 25286 / 35,416 |
71% 9030 hom |
Remaining individuals 4999 / 7,178 |
70% 1753 hom |
East Asian 11314 / 19,918 |
57% 3235 hom |
South Asian 15313 / 30,614 |
50% 3897 hom |
African/African American 9317 / 24,432 |
38% 1785 hom |
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links