LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-17
Case ID: NM_000546.5_c.469G_T_20260417_183300
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.469G>T

TP53  · NP_000537.3:p.(Val157Phe)  · NM_000546.5
GRCh37: chr17:7578461 C>A  ·  GRCh38: chr17:7675143 C>A
Gene: TP53 Transcript: NM_000546.5
Final call
Likely Pathogenic
PS3_Strong PM1_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.(Val157Phe)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.469G>T (p.Val157Phe) variant has been observed in somatic cancers in COSMIC (COSV52667015; n=366) and has not been reported in ClinVar.
2
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 PM2_Supporting threshold of less than 0.00003.
3
TP53 expert panel functional data classify p.Val157Phe as PS3 because the variant is non-functional in Kato, shows loss of function in Funk and Kotler, and is loss-of-function by the majority of eligible assays.
4
Cancer Hotspots shows p.Val157Phe in 67 tumors at the significant TP53 V157 hotspot residue (77 tumors at the residue overall), supporting PM1, while the TP53 bioinformatic worksheet assigns no PP3/BP4 evidence and SpliceAI predicts no splice impact (max delta score 0.00).
Final determination: The combination of PS3_Strong, PM1_Moderate, and PM2_Supporting yields 7 points, meeting the TP53 point-based threshold for Likely Pathogenic.
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 is a missense variant, so the TP53 null-variant PVS1 framework does not apply.
cspec vcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PS1 Not assessed No evidence was identified that a different nucleotide change causing the same p.Val157Phe amino acid substitution has already been classified as pathogenic or likely pathogenic under TP53 VCEP specifications.
cspec clinvar
PS2 Not assessed No confirmed de novo observations with validated maternity and paternity were identified, so PS2 cannot be assessed.
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 Met TP53 expert panel functional data classify p.Val157Phe as PS3. The variant is non-functional in Kato, shows loss of function in Funk and Kotler, and is loss-of-function by the majority of eligible assays, which supports damaging protein function.
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 oncokb
PS4 Not assessed No germline proband data meeting TP53 PS4 point-based criteria were identified. Somatic observations in cancer databases do not establish the required Li-Fraumeni syndrome case-point evidence.
cspec vcep_p_s_4___p_o_i_n_t_s___t_a_b_l_e cosmic
PM1 Met This missense variant affects TP53 codon 157, a statistically significant hotspot residue in Cancer Hotspots. The exact amino acid change p.Val157Phe is reported 67 times, which is above the TP53 PM1 threshold of at least 10 somatic occurrences for the same amino acid change.
hotspots
PM2 Met This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 PM2_Supporting threshold of less than 0.00003.
gnomad_v2 gnomad_v4 cspec
PM3 N/A PM3 is not applicable for TP53 under this VCEP framework.
cspec
PM4 N/A PM4 is not applicable for TP53 under this VCEP framework.
cspec
PM5 Not assessed No evidence was identified that another missense change at codon 157 has already been classified as pathogenic or likely pathogenic under TP53 VCEP specifications in a way that supports PM5.
cspec clinvar
PM6 N/A PM6 is not applicable for TP53 under this VCEP framework.
cspec
PP1 Not assessed No segregation data were identified, so PP1 cannot be assessed.
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 for TP53 under this VCEP framework.
cspec
PP3 Not met TP53 bioinformatic pre-assignment does not support PP3 for this missense change. In the TP53 PP3/BP4 worksheet, c.469G>T (p.Val157Phe) is assigned 'No evidence,' and SpliceAI predicts no splice impact with a maximum delta score of 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 constitutional mosaicism evidence were identified, so the TP53-specific PP4 criteria cannot be assessed.
cspec
PP5 N/A PP5 is not used by the TP53 VCEP.
cspec
BA1 Not met Population frequency does not meet BA1. The variant is absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 BA1 threshold of filtering allele frequency at or above 0.001.
gnomad_v4 cspec
BS1 Not met Population frequency does not meet BS1. The variant is absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 BS1 threshold of filtering allele frequency at or above 0.0003.
gnomad_v4 cspec
BS2 Not assessed No dataset of unrelated females aged 60 years or older without cancer who carry this variant was identified, so BS2 cannot be assessed.
cspec
BS3 Not met Available functional evidence does not support BS3. TP53 expert panel functional data assign PS3, not BS3, because p.Val157Phe is non-functional in Kato and shows loss of function in the majority of eligible assays.
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
BS4 Not assessed No lack-of-segregation data in relatives with Li-Fraumeni syndrome-associated cancers were identified, so BS4 cannot be assessed.
cspec
BP1 N/A BP1 is not applicable for TP53 under this VCEP framework.
cspec
BP2 N/A BP2 is not applicable for TP53 under this VCEP framework.
cspec
BP3 N/A BP3 is not applicable for TP53 under this VCEP framework.
cspec
BP4 Not met TP53 bioinformatic pre-assignment does not support BP4 for this missense change. In the TP53 PP3/BP4 worksheet, c.469G>T (p.Val157Phe) is assigned 'No evidence,' and SpliceAI predicts no splice impact with a maximum delta score of 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___p_b_7 spliceai
BP5 N/A BP5 is not applicable for TP53 under this VCEP framework.
cspec
BP6 N/A BP6 is not used by the TP53 VCEP.
cspec
BP7 N/A BP7 applies to synonymous or qualifying intronic variants, whereas this is a missense 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
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.