Variant classification summary

NM_000546.6:c.722C>A

TP53 · NP_000537.3:p.(Ser241Tyr) · NM_000546.6

GRCh37: chr17:7577559 G>T · GRCh38: chr17:7674241 G>T

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3_Strong PP3_Moderate PM2_Supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Ser241Tyr)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 NM_000546.6:c.722C>A (p.Ser241Tyr, p.S241Y) variant has been observed in somatic cancers in COSMIC (COSV52713934, 54 occurrences) and has been reported in ClinVar as Pathogenic by 4 clinical laboratories and Likely Pathogenic by 1 clinical laboratory.

2

This variant is absent from gnomAD v2.1 and has 0/1,613,928 alleles in gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.

3

TP53 VCEP functional data support loss of p53 function for p.Ser241Tyr, with non-functional Kato results and loss of function in the majority of other eligible assays, supporting PS3.

4

TP53-specific in silico evidence supports a deleterious effect, with Align-GVGD Class C65, BayesDel 0.544682, a pre-assigned PP3_moderate code, and SpliceAI showing no significant predicted splice impact (max delta score 0.01).

Final determination: Likely Pathogenic based on 7 Tavtigian points from PS3_Strong (+4), PP3_Moderate (+2), and PM2_Supporting (+1), which falls within the TP53 VCEP Likely Pathogenic range of 6 to 9 points.

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	NM_000546.6:c.722C>A (p.Ser241Tyr) is a missense variant in exon 7 and does not fall into the TP53 null-variant categories used for PVS1. The TP53-specific PVS1 framework and the generic PVS1 scaffold do not support PVS1 for this variant type.	pvs1_gene_context pvs1_variant_assessment vcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PS1	Not assessed	No reviewed evidence identified a different nucleotide change producing the same amino acid substitution that has already been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications, so PS1 was not applied.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 was not applied.	screen_PS4.json 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	Functional studies compiled in the TP53 VCEP functional worksheet show that p.Ser241Tyr is non-functional in Kato, shows loss of function in Funk and Kotler, and has loss of function in the majority of other eligible assays despite a noLOF result in Giacomelli. This pattern meets the TP53 VCEP rule for PS3 at strong strength.	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	This variant has been reported in germline disease databases and in somatic cancers, but the reviewed materials did not provide a TP53 VCEP point-based count of independent probands with Li-Fraumeni syndrome-associated cancers sufficient to assign PS4. Therefore PS4 was not applied in this pass.	clinvar cosmic screen_PS4.json vcep_p_s_4___p_o_i_n_t_s___t_a_b_l_e
PM1	Not assessed	TP53 codon 241 is not one of the predefined TP53 VCEP hotspot codons for automatic PM1 application, and the reviewed Cancer Hotspots result was marked uncertain without a confirmed exact-variant count. Because the hotspot evidence was not fully validated, PM1 was not applied.	hotspots cspec
PM2	Met	This variant is absent from gnomAD v2.1 and has 0/1,613,928 alleles in gnomAD v4.1, with no alleles observed in the largest reported subpopulation. The observed allele frequency of 0 is below the TP53 VCEP PM2_Supporting threshold of 0.00003, so PM2 is met at supporting strength.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework for this gene-disease context.	cspec
PM4	N/A	PM4 is not applicable in the TP53 VCEP framework for this gene-disease context.	cspec
PM5	Not assessed	No reviewed source established that one or more different missense variants at codon Ser241 have already been determined to be pathogenic or likely pathogenic using the TP53 VCEP specifications, so PM5 was not applied.	clinvar cspec
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework for this gene-disease context.	cspec
PP1	Not assessed	No segregation data showing cosegregation with Li-Fraumeni syndrome-associated cancers across informative meioses were identified for this variant, so PP1 was not applied.	screen_PP1.json 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 for this gene-disease context.	cspec
PP3	Met	The TP53 VCEP PP3/BP4 worksheet lists NM_000546.6:c.722C>A (p.Ser241Tyr) as Align-GVGD Class C65 with a BayesDel score of 0.544682 and a preliminary code of PP3_moderate. SpliceAI shows a maximum delta score of 0.01, which is below the 0.2 threshold for predicted splice impact, so the missense prediction remains applicable and PP3 is met at moderate strength.	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
PP4	Not assessed	No evidence was identified that this variant was observed at a low blood variant allele fraction in one or more individuals in a manner meeting the TP53 VCEP mosaicism-based PP4 criteria, so PP4 was not applied.	cspec
PP5	N/A	PP5 is not for use in the TP53 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and has 0/1,613,928 alleles in gnomAD v4.1, so its frequency is far below the TP53 VCEP BA1 threshold of 0.001. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and has 0/1,613,928 alleles in gnomAD v4.1, so its frequency is below the TP53 VCEP BS1 threshold of 0.0003. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No reviewed source documented unrelated females aged 60 years or older without cancer who carry this variant from a single source, so BS2 was not applied.	clinvar cspec
BS3	Not met	Available functional evidence does not show normal or partially retained TP53 function. Instead, the TP53 VCEP functional worksheet assigns p.Ser241Tyr a preliminary code of PS3, 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
BS4	Not assessed	No lack-of-segregation evidence in affected relatives with Li-Fraumeni syndrome-associated cancers was identified for this variant, so BS4 was not applied.	screen_BS4.json 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 for this gene-disease context.	cspec
BP2	N/A	BP2 is not applicable in the TP53 VCEP framework for this gene-disease context.	cspec
BP3	N/A	BP3 is not applicable in the TP53 VCEP framework for this gene-disease context.	cspec
BP4	Not met	Bioinformatic evidence does not support a benign interpretation. The TP53 VCEP PP3/BP4 worksheet assigns this missense change PP3_moderate based on Align-GVGD Class C65 and BayesDel 0.544682, and SpliceAI predicts no splice rescue effect (max delta score 0.01), so BP4 is not met.	vcep_p_p_3___b_p_4___c_o_d_e_s spliceai
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework for this gene-disease context.	cspec
BP6	N/A	BP6 is not for use in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants without predicted splice impact, whereas NM_000546.6:c.722C>A is a missense variant. BP7 is therefore 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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