Variant classification summary

NM_000546.5:c.215C>G

TP53 · NP_000537.3:p.(Pro72Arg) · NM_000546.5

GRCh37: chr17:7579472 G>C · GRCh38: chr17:7676154 G>C

Gene: TP53 Transcript: NM_000546.5

Final call

Benign

BA1 stand-alone benign BP4 moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Pro72Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -10, which maps to Benign under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This missense variant does not create a predicted null allele and is not a canonical +/-1,2 splice-site change, so PVS1 does not apply.	pvs1_variant_assessment cspec
PS1	Not assessed	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.	cspec clinvar
PS2	Not assessed	No confirmed de novo observations were identified for this variant, so PS2 cannot be applied.	cspec vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
PS3	Not met	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.	vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_t vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___f_u_n_c_t_i_o_n_a_l___r_u_l_e___c_o_d_e_s PMID:10802655 PMID:12567188 PMID:16964264
PS4	Not met	Available evidence does not show enrichment of this variant in individuals with TP53-related disease. The variant is extremely common in population databases and is classified as benign by the ClinGen TP53 expert panel, so PS4 is not met.	clinvar gnomad_v2 gnomad_v4 cspec
PM1	Not met	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.	hotspots cspec
PM2	Not met	Population frequency is far above the TP53 VCEP PM2 threshold. In gnomAD v4.1 the total allele frequency is 0.707882 and the highest observed population frequency is 0.747582, whereas PM2 requires a total frequency below 0.00003 and below 0.00004 within any ancestry group with multiple alleles.	gnomad_v4 gnomad_v2 cspec
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework for this disorder context.	cspec
PM4	N/A	PM4 is not applicable because this is not a protein length-changing variant and TP53 VCEP does not use PM4 in this context.	cspec
PM5	Not assessed	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.	cspec clinvar
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
PP2	N/A	PP2 is not applicable in the TP53 VCEP framework.	cspec
PP3	Not met	TP53 VCEP in silico data do not support a damaging effect. In the TP53 PP3/BP4 worksheet, c.215C>G is assigned BP4_moderate with BayesDel -0.108475, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, so PP3 is not met.	vcep_p_p_3___b_p_4___c_o_d_e_s spliceai vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7 cspec
PP4	Not assessed	No qualifying low-variant-allele-fraction observation was identified, so the TP53-specific PP4 criterion was not applied.	cspec
PP5	N/A	PP5 is not applicable in the TP53 VCEP framework.	cspec
BA1	Met	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 gnomad_v2 cspec
BS1	Not assessed	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.	gnomad_v4 gnomad_v2 cspec
BS2	Not assessed	No single-source series of unaffected older female carriers was identified, so BS2 cannot be applied.	cspec
BS3	Not met	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.	vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_t vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___f_u_n_c_t_i_o_n_a_l___r_u_l_e___c_o_d_e_s PMID:10802655 PMID:12567188 PMID:16199549 PMID:17535973 PMID:17638920 PMID:19521721 PMID:21619694
BS4	Not assessed	No family data showing lack of segregation with Li-Fraumeni spectrum cancers were identified, so BS4 cannot be applied.	cspec vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
BP1	N/A	BP1 is not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not applicable in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable in the TP53 VCEP framework.	cspec
BP4	Met	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.	vcep_p_p_3___b_p_4___c_o_d_e_s spliceai vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7 cspec
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not applicable in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic variant.	cspec vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7

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