Classification rationale

PS3PM2PP3 Likely Pathogenic

TP53 c.722C>A

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.¹ 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 0.00003.² 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 PS3.³ 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).⁴

PS3 + PM2 + PP3 → Likely Pathogenic

1 cosmic ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_toncokb ↗PMID:12826609 ↗PMID:29979965PMID:30224644PMID:25584008 ↗

4 vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000546.6 · variants mapped to exon structure

TP53 NM_000546.6

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PS3 Strong Pathogenic

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.

oncokb ↗

PM2 Supporting Pathogenic

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 v2.1: absent.gnomAD v4.1: 0/1613928 alleles, AF 0.0; African/African American 0/74982 alleles, AF 0.0.

gnomad_v2 ↗gnomad_v4 ↗

PP3 Moderate Pathogenic

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.

spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 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.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 was not applied.

PS4 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.

PM1 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.

PM5 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.

PP1 No segregation data showing cosegregation with Li-Fraumeni syndrome-associated cancers across informative meioses were identified for this variant, so PP1 was not applied.

PP4 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.

Benign

BA1 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.

BS1 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.

BS2 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.

BS3 Available functional evidence does not show normal or partially retained TP53 function.

BS4 No lack-of-segregation evidence in affected relatives with Li-Fraumeni syndrome-associated cancers was identified for this variant, so BS4 was not applied.

BP4 Bioinformatic evidence does not support a benign interpretation.

N/A · 12 PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613928 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74982 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,613,928
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52713934, n = 54 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

6papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Understanding the function-structure and function-mutation relationships of p53

PMID 12826609 ↗

Found