TP53c.469G>TLikely pathogenic

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Variant interpretation report

TP53 c.469G>T, p.(Val157Phe)

NM_000546.5:c.469G>T NP_000537.3:p.(Val157Phe) View identifiers

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.

About TP53

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): 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.
PM1 (moderate): 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.
PM2 (supporting): 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.

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

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.

PM1Moderate

PM1 · moderate

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.

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

TP53 VCEP v2.4.0 CSPEC point-based final-classification framework (Tavtigian et al., 2020 Bayesian adaptation): PS3_Strong (4) + PM1_Moderate (2) + PM2_Supporting (1) = 7 points, which falls in the 6-9 point range for Likely Pathogenic.

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 / 1,614,132 alleles

gnomAD v4.1: 0 / 1,614,132 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗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.

No listed criterion applied

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: Likely Loss-of-function.

Applied · PS3 → OncoKB ↗

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 Cancer Hotspots ↗

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 · 5 not met · 8 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

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.

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).

Met · 3

PS3 StrongTP53 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. Details ▾Hide ▴

Rule

Non-functional on Kato et al. data and loss of function by the majority of other eligible assays.

Evidence considered

Functional-worksheet.xlsx: V157F | NA | Non-functional | LOF | noLOF | LOF | NA | PS3
OncoKB: Likely 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 ↗PMID:15037740 ↗PMID:16778209 ↗PMID:21561095 ↗

PM1 ModerateThis 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. Details ▾Hide ▴

Rule

Missense variants with at least 10 somatic occurrences for the same amino acid change in cancerhotspots.org.

Evidence considered

Cancer Hotspots residue V157: tumorCount 77, qValue 1.04043861763858e-43
Cancer Hotspots exact variant V157F: 67 tumors

Sources

hotspots ↗

PM2 SupportingThis 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. Details ▾Hide ▴

Rule

Apply at supporting level when allele frequency is less than 0.00003 in gnomAD or another large sequenced population.

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: 0/1614132 alleles, AF 0.0

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not met · 5 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴

Rule

TP53 PP3 for missense variants requires a qualifying precomputed in silico assignment or predicted splice effect.

Evidence considered

PP3-BP4-codes.xlsx: c.469G>T | p.Val157Phe | Class C0 | 0.314073 | No evidence
SpliceAI max delta score: 0.00

Sources

vcep_p_p_3___b_p_4___c_o_d_e_svcep_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_7spliceai ↗

BA1 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. Details ▾Hide ▴

Rule

Filtering allele frequency at or above 0.001 in an eligible gnomAD continental subpopulation.

Evidence considered

gnomAD v4.1: 0/1614132 alleles, AF 0.0

Sources

gnomad_v4 ↗cspec ↗

BS1 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. Details ▾Hide ▴

Rule

Filtering allele frequency at or above 0.0003 but below 0.001 in an eligible gnomAD continental subpopulation.

Evidence considered

gnomAD v4.1: 0/1614132 alleles, AF 0.0

Sources

gnomad_v4 ↗cspec ↗

BS3 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. Details ▾Hide ▴

Rule

BS3 requires functional or partially functional assay results without loss of function by eligible assays.

Evidence considered

Functional-worksheet.xlsx: V157F preliminary functional code = PS3

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_sPMID:15037740 ↗PMID:16778209 ↗PMID:21561095 ↗

BP4 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. Details ▾Hide ▴

Rule

TP53 BP4 for missense variants requires a qualifying benign precomputed in silico assignment and no predicted splice effect.

Evidence considered

PP3-BP4-codes.xlsx: c.469G>T | p.Val157Phe | Class C0 | 0.314073 | No evidence
SpliceAI max delta score: 0.00

Sources

vcep_p_p_3___b_p_4___c_o_d_e_svcep_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_7spliceai ↗

Not assessed · 8 · no assessment recorded

PS1 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. Details ▾Hide ▴

Evidence considered

ClinVar: absent

Still missing

No TP53 VCEP pathogenic or likely pathogenic same-amino-acid comparator variant was identified.

Sources

cspec ↗clinvar ↗

PS2 No confirmed de novo observations with validated maternity and paternity were identified, so PS2 cannot be assessed. Details ▾Hide ▴

Still missing

No de novo case-level data were identified.

Sources

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

PS4 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. Details ▾Hide ▴

Evidence considered

COSMIC: somatic count 366

Still missing

No eligible germline case observations with TP53 PS4 point totals were identified.

Sources

cspec ↗vcep_p_s_4___p_o_i_n_t_s___t_a_b_l_ecosmic

PM5 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. Details ▾Hide ▴

Evidence considered

ClinVar: absent

Still missing

No qualifying TP53 VCEP codon-matched pathogenic or likely pathogenic comparator variant was identified.

Sources

cspec ↗clinvar ↗

PP1 No segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴

Still missing

No family segregation data were identified.

Sources

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

PP4 No blood variant allele fraction data or constitutional mosaicism evidence were identified, so the TP53-specific PP4 criteria cannot be assessed. Details ▾Hide ▴

Still missing

No qualifying VAF-based observation data were identified.

Sources

cspec ↗

BS2 No dataset of unrelated females aged 60 years or older without cancer who carry this variant was identified, so BS2 cannot be assessed. Details ▾Hide ▴

Still missing

No qualifying unaffected carrier dataset from a single source was identified.

Sources

cspec ↗

BS4 No lack-of-segregation data in relatives with Li-Fraumeni syndrome-associated cancers were identified, so BS4 cannot be assessed. Details ▾Hide ▴

Still missing

No informative segregation data were identified.

Sources

cspec ↗

Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant, so the TP53 null-variant PVS1 framework does not apply. Details ▾Hide ▴

Evidence considered

NM_000546.5:c.469G>T
NP_000537.3:p.(Val157Phe)

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous or qualifying intronic variants, whereas this is a missense variant. Details ▾Hide ▴

Evidence considered

NM_000546.5:c.469G>T
NP_000537.3:p.(Val157Phe)

Sources

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

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.469G>T
Protein (HGVS p.): NP_000537.3:p.(Val157Phe)
GRCh38: chr17:7675143 C>A
GRCh37: chr17:7578461 C>A

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.

TP53NM_000546.5

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 0 / 1,614,132 alleles AF 0 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,614,132 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%, 0/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75036 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

TP53 PP3 for missense variants requires a qualifying precomputed in silico assignment or predicted splice effect.

Evidence considered

PP3-BP4-codes.xlsx: c.469G>T | p.Val157Phe | Class C0 | 0.314073 | No evidence
SpliceAI max delta score: 0.00

Sources

vcep_p_p_3___b_p_4___c_o_d_e_svcep_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_7spliceai ↗

Rule

TP53 BP4 for missense variants requires a qualifying benign precomputed in silico assignment and no predicted splice effect.

Evidence considered

PP3-BP4-codes.xlsx: c.469G>T | p.Val157Phe | Class C0 | 0.314073 | No evidence
SpliceAI max delta score: 0.00

Sources

vcep_p_p_3___b_p_4___c_o_d_e_svcep_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_7spliceai ↗

BP7 N/ABP7 applies to synonymous or qualifying intronic variants, whereas this is a missense variant. Details ▾Hide ▴

Evidence considered

NM_000546.5:c.469G>T
NP_000537.3:p.(Val157Phe)

Sources

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

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 / 1,614,132 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

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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667015, n = 366 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.