About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.722C>A, p.(Ser241Tyr)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
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.
PM2Supporting
PM2 · supporting
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.
PP3Moderate
PP3 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Official TP53 VCEP/CSPEC v2.4.0 point-based final-classification framework (Tavtigian et al., 2020 Bayesian adaptation of ACMG/AMP) was applied to the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,613,928 alleles
gnomAD v4.1: 0 / 1,613,928 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 3
PS3 StrongFunctional 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. Details ▾Hide ▴
Rule
TP53 VCEP PS3: non-functional on Kato data and loss of function by the majority of other eligible assays.
Evidence considered
- Functional worksheet entry: S241Y | Kato Non-functional | Funk LOF | Giacomelli noLOF | Kotler LOF | Preliminary functional code PS3.
- OncoKB describes the variant as Likely Oncogenic with biological effect Loss-of-function.
Sources
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tvcep_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_soncokb ↗12826609299799653022464425584008
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: allele frequency <0.00003 in a large population dataset.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 0/1613928 alleles, AF 0.0; African/African American 0/74982 alleles, AF 0.0.
Sources
PP3 ModerateThe 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. Details ▾Hide ▴
Rule
TP53 VCEP PP3_Moderate: missense variant with aGVGD Class C65 and BayesDel score ≥0.16, with no predicted splice impact overriding the missense assessment.
Evidence considered
- PP3-BP4 worksheet entry: c.722C>A | p.Ser241Tyr | Align-GVGD Class C65 | BayesDel 0.544682 | PP3_moderate | Max SpliceAI 0.01.
- SpliceAI max delta score 0.01 indicates no significant predicted splice impact.
Sources
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗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_7156514328279309
Not met · 4 · evaluated, threshold not reached
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. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF 0.0; no observed alleles in reviewed subpopulations.
Sources
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. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF 0.0; no observed alleles in reviewed subpopulations.
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- Functional worksheet entry for S241Y is preassigned PS3 rather than BS3.
Sources
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tvcep_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_s128266092997996530224644
BP4 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. Details ▾Hide ▴
Evidence considered
- c.722C>A is listed as PP3_moderate in the TP53 PP3/BP4 worksheet.
- SpliceAI max delta score is 0.01.
Sources
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗
Not assessed · 9 · no assessment recorded
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. Details ▾Hide ▴
Evidence considered
- ClinVar contains this variant, but the reviewed materials did not document another nucleotide change encoding the same amino acid substitution with a TP53 VCEP-based classification.
Still missing
- A residue-level search for alternative codon changes causing p.Ser241Tyr under TP53 VCEP assertions was not available in the reviewed sources.
Sources
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 was not applied. Details ▾Hide ▴
Evidence considered
- No source provided a TP53 VCEP PS2 point total for this variant.
Still missing
- No proband-specific de novo documentation or point tally was available in the reviewed evidence.
Sources
screen_PS4.jsonvcep_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_n32817165
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. Therefore PS4 was not applied in this pass. Details ▾Hide ▴
Evidence considered
- ClinVar reports Pathogenic/Likely Pathogenic submissions for this variant.
- COSMIC reports somatic observation COSV52713934 with 54 occurrences.
- Screened literature identified possible case-observation sources but did not provide a validated TP53 PS4 point total.
Still missing
- Variant-specific germline proband count and cancer-type point total under the TP53 VCEP PS4 framework were not established from the reviewed sources.
Sources
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. Because the hotspot evidence was not fully validated, PM1 was not applied. Details ▾Hide ▴
Evidence considered
- TP53 VCEP automatic hotspot codons are 175, 245, 248, 249, 273, and 282.
- Cancer Hotspots review for S241Y was flagged as uncertain and needs human review.
Still missing
- Confirmed Cancer Hotspots exact-variant count for p.Ser241Tyr was not established from the reviewed materials.
Sources
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. Details ▾Hide ▴
Evidence considered
- The reviewed files did not provide TP53 VCEP-based residue-level adjudications for alternative missense changes at Ser241.
Still missing
- Residue-level TP53 VCEP adjudications for other Ser241 missense substitutions were not available in the reviewed materials.
Sources
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. Details ▾Hide ▴
Evidence considered
- The reviewed evidence did not document 3 or more informative meioses supporting cosegregation.
Still missing
- No family-level meiosis count was available for TP53 VCEP PP1 scoring.
Sources
screen_PP1.jsonvcep_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_n32817165
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. Details ▾Hide ▴
Evidence considered
- The reviewed evidence did not provide low-VAF blood observations or supporting mosaicism data for this variant.
Still missing
- Variant allele fraction and tissue-confirmation data were not available in the reviewed materials.
Sources
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. Details ▾Hide ▴
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. Details ▾Hide ▴
Evidence considered
- No reviewed report documented lack of segregation in affected relatives.
Still missing
- Family-level data demonstrating nonsegregation were not available in the reviewed materials.
Sources
screen_BS4.jsonvcep_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_n32817165
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- TP53 is eligible for gene-specific PVS1 assessment, but this variant is not a nonsense, frameshift, or canonical ±1,2 splice variant.
- pvs1_variant_assessment.json states that this variant does not fall into default generic PVS1 null-variant buckets.
Sources
pvs1_gene_contextpvs1_variant_assessmentvcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PM3 N/APM3 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
PM4 N/APM4 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
PM6 N/APM6 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
PP5 N/APP5 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
BP2 N/ABP2 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
BP5 N/ABP5 is not applicable in the TP53 VCEP framework for this gene-disease context. Details ▾Hide ▴
BP6 N/ABP6 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- This variant changes p.Ser241Tyr and is not synonymous or intronic.
Sources
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
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.722C>A
- Protein (HGVS p.)
- NP_000537.3:p.(Ser241Tyr)
- GRCh38
- chr17:7674241 G>T
- GRCh37
- chr17:7577559 G>T
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.
TP53NM_000546.6
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
0 / 1,613,928 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,613,928 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD 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).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ModerateThe 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. Details ▾Hide ▴
Rule
TP53 VCEP PP3_Moderate: missense variant with aGVGD Class C65 and BayesDel score ≥0.16, with no predicted splice impact overriding the missense assessment.
Evidence considered
- PP3-BP4 worksheet entry: c.722C>A | p.Ser241Tyr | Align-GVGD Class C65 | BayesDel 0.544682 | PP3_moderate | Max SpliceAI 0.01.
- SpliceAI max delta score 0.01 indicates no significant predicted splice impact.
Sources
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗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_7156514328279309
BP4 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. Details ▾Hide ▴
Evidence considered
- c.722C>A is listed as PP3_moderate in the TP53 PP3/BP4 worksheet.
- SpliceAI max delta score is 0.01.
Sources
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- This variant changes p.Ser241Tyr and is not synonymous or intronic.
Sources
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
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,613,928 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/376663/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577559-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7674241-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.722C…
- OncoKB ↗www.oncokb.org/gene/TP53/S241Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104370807
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52713934, n = 54 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.