LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-17
Case ID: NM_000546.5_c.764T_A_20260417_021659
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.764T>A

TP53  · NP_000537.3:p.(Ile255Asn)  · NM_000546.5
GRCh37: chr17:7577517 A>T  ·  GRCh38: chr17:7674199 A>T
Gene: TP53 Transcript: NM_000546.5
Final call
Likely Pathogenic
PS3_Strong PP3_Moderate PM2_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.5
Protein
NP_000537.3:p.(Ile255Asn)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.764T>A (p.Ile255Asn; p.I255N) variant has been observed in somatic cancers in COSMIC (COSV52714133, 23 occurrences) and has not been reported in ClinVar.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the TP53 PM2_Supporting threshold of less than 0.00003.
3
TP53 functional assay evidence supports loss of function, as the TP53 VCEP Functional-worksheet lists I255N as non-functional in Kato and loss-of-function in the other eligible assays shown, consistent with PS3.
4
TP53 in silico evidence supports a damaging effect because the TP53 PP3/BP4 worksheet assigns c.764T>A (p.Ile255Asn) as PP3_moderate with BayesDel 0.347565, while SpliceAI predicts no significant splice impact (max delta score 0.00).
Final determination: PS3_Strong, PP3_Moderate, and PM2_Supporting yield a total of 7 Tavtigian points, consistent with a Likely Pathogenic classification.
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 variant is a missense change, p.(Ile255Asn), and is not a null, canonical splice-site, frameshift, nonsense, initiation-codon, or exon-level loss-of-function variant. SpliceAI shows no predicted splice effect (max delta score 0.00), so the TP53 PVS1 framework is not applicable.
spliceai vcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PS1 Not assessed No previously established TP53 VCEP pathogenic or likely pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 cannot be determined from the current data.
clinvar cspec
PS2 Not assessed No confirmed de novo data, parentage confirmation, or proband cancer-point information was identified, so PS2 cannot be applied.
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 Met TP53 functional data support loss of function for p.(Ile255Asn). In the TP53 VCEP Functional-worksheet, I255N is listed as non-functional in Kato and as loss-of-function in the other eligible assays shown, which meets the TP53 PS3 strong rule.
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:12826609 PMID:29979965 PMID:30224644
PS4 Not assessed This variant meets PM2_Supporting based on population data, but no germline Li-Fraumeni syndrome case observations or PS4 point-based evidence were identified, so PS4 cannot be scored.
gnomad_v2 gnomad_v4 vcep_p_s_4___p_o_i_n_t_s___t_a_b_l_e
PM1 Not assessed This missense variant affects codon 255, which is not one of the predefined TP53 major hotspot codons (175, 245, 248, 249, 273, 282). Cancer Hotspots review for p.(Ile255Asn) was flagged as uncertain, so the same-amino-acid-change occurrence threshold needed for TP53 PM1 could not be confirmed from the available evidence.
hotspots cspec
PM2 Met This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the TP53 PM2_Supporting threshold of less than 0.00003 overall and below 0.00004 within any ancestry group.
gnomad_v2 gnomad_v4 cspec
PM3 N/A PM3 is not used in the TP53 VCEP framework.
cspec
PM4 N/A PM4 is not used in the TP53 VCEP framework.
cspec
PM5 Not assessed No TP53 VCEP-established pathogenic or likely pathogenic missense comparison variants at codon 255 were identified in the available evidence, so PM5 cannot be determined from the current data.
cspec clinvar
PM6 N/A PM6 is not used in the TP53 VCEP framework.
cspec
PP1 Not assessed No segregation data were identified, so PP1 cannot be applied.
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 used in the TP53 VCEP framework.
cspec
PP3 Met TP53 in silico evidence supports a damaging effect for this missense variant. In the TP53 PP3/BP4 worksheet, c.764T>A (p.Ile255Asn) is assigned Class C65 with BayesDel 0.347565 and a precomputed code of PP3_moderate; SpliceAI shows no splice effect (max delta score 0.00).
vcep_p_p_3___b_p_4___c_o_d_e_s 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 spliceai
PP4 Not assessed No blood variant allele fraction data or qualifying low-level mosaic observations were identified, so PP4 cannot be applied.
cspec
PP5 N/A PP5 is not used in the TP53 VCEP framework.
cspec
BA1 Not met This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0, which is below the TP53 BA1 threshold of at least 0.001.
gnomad_v2 gnomad_v4 cspec
BS1 Not met This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0, which is below the TP53 BS1 threshold of at least 0.0003.
gnomad_v2 gnomad_v4 cspec
BS2 Not assessed No data were identified showing this variant in unrelated females aged at least 60 years without cancer from a single source, so BS2 cannot be applied.
cspec
BS3 Not met Available functional evidence does not support normal TP53 protein function. The TP53 VCEP Functional-worksheet lists I255N as non-functional in Kato and loss-of-function in the other eligible assays shown, which argues against BS3.
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:12826609 PMID:29979965 PMID:30224644
BS4 Not assessed No data showing lack of segregation in affected family members were identified, so BS4 cannot be applied.
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 used in the TP53 VCEP framework.
cspec
BP2 N/A BP2 is not used in the TP53 VCEP framework.
cspec
BP3 N/A BP3 is not used in the TP53 VCEP framework.
cspec
BP4 Not met Available TP53 in silico evidence does not support a benign computational prediction. The TP53 PP3/BP4 worksheet assigns c.764T>A (p.Ile255Asn) a BayesDel score of 0.347565 with a precomputed code of PP3_moderate, and SpliceAI shows no splice effect (max delta score 0.00), so BP4 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
BP5 N/A BP5 is not used in the TP53 VCEP framework.
cspec
BP6 N/A BP6 is not used in the TP53 VCEP framework.
cspec
BP7 N/A BP7 applies to synonymous or qualifying intronic variants. This variant is a missense change, so BP7 is not applicable.
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
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