Variant classification summary

NM_000546.6:c.833C>A

TP53 · NP_000537.3:p.(Pro278His) · NM_000546.6

GRCh37: chr17:7577105 G>T · GRCh38: chr17:7673787 G>T

Gene: TP53 Transcript: NM_000546.6

Final call

PS3 PP3_Moderate PM2_Supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Pro278His)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

TP53 p.Pro278His has abnormal functional evidence, and the TP53 VCEP functional worksheet assigns PS3 for this amino acid substitution.

2

TP53 in silico assessment assigns c.833C>A as PP3_Moderate, with BayesDel 0.607821 and Class C65 supporting a deleterious missense effect.

3

SpliceAI predicts a max delta score of 0.00, which is below the TP53 splice-impact threshold of 0.2 and does not indicate a predicted splice effect.

4

The variant is absent from gnomAD v4.1, and absence from population databases is consistent with the TP53 PM2_Supporting threshold of less than 0.00003.

5

Using the generic ACMG/AMP combination rules as a fallback because explicit TP53 VCEP final Tavtigian score thresholds were not explicitly retrieved, PS3 with PP3_Moderate and PM2_Supporting supports a Likely Pathogenic classification.

Final determination:

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	PVS1 is not applicable because NM_000546.6:c.833C>A is a missense variant, not a null or canonical splice variant addressed by the TP53 PVS1 framework.	cspec vcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PS1	Not assessed	PS1 was not assessed because no TP53 VCEP-classified pathogenic or likely pathogenic variant producing the same amino acid change was explicitly retrieved.	cspec
PS2	Not assessed	PS2 was not assessed because no de novo data, parental testing, or proband point tally was provided.	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	The TP53 VCEP functional worksheet lists P278H with a final functional assignment of PS3.	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 cspec
PS4	Not assessed	PS4 was not assessed because no germline proband-based Li-Fraumeni syndrome point data were retrieved.	cspec vcep_p_s_4___p_o_i_n_t_s___t_a_b_l_e
PM1	Not assessed	PM1 was not applied because codon 278 is not one of the TP53 codons with automatic PM1 at moderate strength, and the available hotspot evidence did not explicitly provide a cancerhotspots.org same-amino-acid count meeting the TP53 PM1 threshold.	cspec oncokb
PM2	Met	The variant is absent from gnomAD v2.1 and gnomAD v4.1, 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 under the TP53 specifications.	cspec
PM4	N/A	PM4 is not applicable because this is a missense substitution rather than a protein length-changing in-frame indel or stop-loss variant.	cspec
PM5	Not assessed	PM5 was not assessed because no explicitly retrieved TP53 VCEP-classified pathogenic or likely pathogenic alternate missense variant at codon 278 was available.	cspec
PM6	N/A	PM6 is not applicable under the TP53 specifications.	cspec
PP1	Not assessed	PP1 was not assessed because no segregation data or meiosis count was provided.	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 under the TP53 specifications.	cspec
PP3	Met	The TP53 VCEP PP3/BP4 worksheet assigns c.833C>A (p.Pro278His) as PP3_moderate with BayesDel score 0.607821 and Class C65; SpliceAI max delta score is 0.00, which is below the 0.2 splice-impact threshold used in the TP53 in silico flowchart.	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 cspec
PP4	Not assessed	PP4 was not assessed because no low-VAF constitutional mosaicism observations were provided.	cspec
PP5	N/A	PP5 is not applicable under the TP53 specifications.	cspec
BA1	Not met	BA1 is not met because the variant is absent from gnomAD and therefore does not reach the TP53 BA1 filtering allele frequency threshold of at least 0.001.	gnomad_v4 cspec
BS1	Not met	BS1 is not met because the variant is absent from gnomAD and therefore does not reach the TP53 BS1 threshold of filtering allele frequency at least 0.0003.	gnomad_v4 cspec
BS2	Not assessed	BS2 was not assessed because no single-source dataset of unrelated cancer-free females aged at least 60 years carrying this variant was provided.	cspec
BS3	Not met	BS3 is not met because the TP53 VCEP functional worksheet assigns PS3 rather than BS3 for P278H, consistent with abnormal functional evidence rather than retained function.	vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_t cspec
BS4	Not assessed	BS4 was not assessed because no nonsegregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were provided.	cspec
BP1	N/A	BP1 is not applicable under the TP53 specifications.	cspec
BP2	N/A	BP2 is not applicable under the TP53 specifications for this review.	cspec
BP3	N/A	BP3 is not applicable under the TP53 specifications.	cspec
BP4	Not met	BP4 is not met because the TP53 VCEP in silico worksheet assigns PP3_moderate, not BP4, for c.833C>A.	vcep_p_p_3___b_p_4___c_o_d_e_s cspec
BP5	N/A	BP5 is not applicable under the TP53 specifications.	cspec
BP6	N/A	BP6 is not applicable under the TP53 specifications.	cspec
BP7	N/A	BP7 is not applicable 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

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.