TP53c.1031T>CLikely pathogenic

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Variant interpretation report

TP53 c.1031T>C, p.(Leu344Pro)

NM_000546.5:c.1031T>C NP_000537.3:p.(Leu344Pro) 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) · 2 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): The TP53 VCEP functional worksheet assigns p.Leu344Pro to PS3 based on non-functional activity in the Kato framework, loss-of-function results across other eligible assays, and monomeric behavior in the oligomerization domain. Published functional studies for this variant support a damaging loss-of-function effect.
PM2 (supporting): This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07). The highest observed ancestry-specific frequency is 1/91074 in South Asian individuals (AF 1.0980e-05), which is below the TP53 VCEP PM2 threshold of 0.00003 overall and below the 0.00004 ancestry threshold used when multiple alleles are present; PM2_Supporting is met.
PP3 (moderate): The TP53 VCEP PP3/BP4 worksheet assigns c.1031T>C as PP3_moderate with aGVGD Class C65 and BayesDel 0.485604. Additional computational evidence is concordant, including a REVEL score of 0.862, supporting a damaging missense effect.
PP5 (supporting): Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

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: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PS3Strong

PS3 · strong

The TP53 VCEP functional worksheet assigns p.Leu344Pro to PS3 based on non-functional activity in the Kato framework, loss-of-function results across other eligible assays, and monomeric behavior in the oligomerization domain. Published functional studies for this variant support a damaging loss-of-function effect.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07). The highest observed ancestry-specific frequency is 1/91074 in South Asian individuals (AF 1.0980e-05), which is below the TP53 VCEP PM2 threshold of 0.00003 overall and below the 0.00004 ancestry threshold used when multiple alleles are present; PM2_Supporting is met.

PP3Moderate

PP3 · moderate

The TP53 VCEP PP3/BP4 worksheet assigns c.1031T>C as PP3_moderate with aGVGD Class C65 and BayesDel 0.485604. Additional computational evidence is concordant, including a REVEL score of 0.862, supporting a damaging missense effect.

PP5Supporting

PP5 · supporting

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) + PP5 supporting (+1) = 8 points, which maps to 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

1 / 1,614,076 alleles

gnomAD v4.1: 1 / 1,614,076 alleles. Recorded AF 6.1955e-07. 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.

Applied · PP3 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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

COSMIC ↗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: 4 met · 4 not met · 9 not assessed · 11 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.1031T>C (p.Leu344Pro; p.L344P) variant has been observed in somatic cancer curation resources and has been reported in ClinVar, including a ClinGen TP53 Variant Curation Expert Panel likely pathogenic assertion.

This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07), with the highest observed population frequency in South Asian individuals of 1/91074 (AF 1.0980e-05), supporting rarity for TP53.

In TP53 functional studies summarized by the TP53 VCEP, p.Leu344Pro showed non-functional activity, loss-of-function behavior across eligible assays, and monomeric oligomerization-domain behavior, supporting a damaging loss-of-function effect.

Computational evidence is concordant with a damaging missense effect, with a TP53 VCEP pre-assigned PP3_moderate call, BayesDel 0.485604, and REVEL 0.862.

Met · 4

PS3 StrongThe TP53 VCEP functional worksheet assigns p.Leu344Pro to PS3 based on non-functional activity in the Kato framework, loss-of-function results across other eligible assays, and monomeric behavior in the oligomerization domain. Published functional studies for this variant support a damaging loss-of-function effect. Details ▾Hide ▴

Rule

TP53 VCEP PS3

Evidence considered

Functional worksheet row: L344P | Non-functional | LOF | Monomer | PS3
TP53 VCEP functional flowchart

Sources

vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:9704930 ↗PMID:19106109 ↗PMID:19454241 ↗PMID:20978130 ↗

PM2 SupportingThis variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07). The highest observed ancestry-specific frequency is 1/91074 in South Asian individuals (AF 1.0980e-05), which is below the TP53 VCEP PM2 threshold of 0.00003 overall and below the 0.00004 ancestry threshold used when multiple alleles are present; PM2_Supporting is met. Details ▾Hide ▴

Rule

TP53 VCEP PM2_Supporting

Evidence considered

gnomAD v2.1 absent
gnomAD v4.1 total AF 6.1955e-07
best subpopulation AF 1.0980e-05

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 ModerateThe TP53 VCEP PP3/BP4 worksheet assigns c.1031T>C as PP3_moderate with aGVGD Class C65 and BayesDel 0.485604. Additional computational evidence is concordant, including a REVEL score of 0.862, supporting a damaging missense effect. Details ▾Hide ▴

Rule

TP53 VCEP PP3_Moderate

Evidence considered

PP3-BP4 worksheet row: c.1031T>C | p.Leu344Pro | Class C65 | 0.485604 | PP3_moderate
REVEL 0.862
BayesDel 0.485604

Still missing

A directly captured SpliceAI score was not available in the retrieved text
although the TP53 VCEP pre-assigned code supports PP3 application.

Sources

vcep_pp3_bp4_codesbayesdelrevelcspec ↗

PP5 SupportingExpert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks PP5 not applicable
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

BA1 The observed population frequency does not reach the TP53 VCEP BA1 threshold of at least 0.001 in a qualifying ancestry group. gnomAD v4.1 shows only 1/1614076 alleles overall (AF 6.1955e-07), so BA1 is not met. Details ▾Hide ▴

Rule

TP53 VCEP BA1

Evidence considered

gnomAD v4.1 total AF 6.1955e-07

Sources

cspec ↗gnomad_v4 ↗

BS1 The observed population frequency is below the TP53 VCEP BS1 threshold of at least 0.0003 in a qualifying ancestry group. gnomAD v4.1 shows only 1/1614076 alleles overall (AF 6.1955e-07), so BS1 is not met. Details ▾Hide ▴

Rule

TP53 VCEP BS1

Evidence considered

gnomAD v4.1 total AF 6.1955e-07

Sources

cspec ↗gnomad_v4 ↗

BS3 Available functional evidence does not show normal or near-normal TP53 function. Instead, the TP53 VCEP functional worksheet assigns this variant to PS3 based on non-functional and loss-of-function results, so BS3 is not met. Details ▾Hide ▴

Rule

TP53 VCEP BS3

Evidence considered

Functional worksheet assigns PS3
not BS3

Sources

vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:9704930 ↗PMID:19106109 ↗PMID:19454241 ↗PMID:20978130 ↗

BP4 Computational evidence does not support a benign effect. The TP53 VCEP PP3/BP4 worksheet assigns PP3_moderate rather than BP4, BayesDel is 0.485604, and REVEL is 0.862, all of which are consistent with a damaging missense effect. Details ▾Hide ▴

Rule

TP53 VCEP BP4

Evidence considered

PP3-BP4 worksheet pre-assigned PP3_moderate
BayesDel 0.485604
REVEL 0.862

Sources

vcep_pp3_bp4_codesbayesdelrevelcspec ↗

Not assessed · 9 · no assessment recorded

PS1 No independently verified evidence was identified showing a different nucleotide change that produces the same p.Leu344Pro amino acid substitution and has already been classified under the TP53 VCEP framework, so PS1 was not applied. Details ▾Hide ▴

Rule

TP53 VCEP PS1

Evidence considered

TP53 VCEP PS1 rule requires an already classified same amino acid change

Still missing

A residue-level search for alternate nucleotide changes encoding p.Leu344Pro would be needed for definitive PS1 assessment.

Sources

cspec ↗clinvar ↗

PS2 No confirmed de novo occurrence with sufficient clinical and parental testing detail was identified, so PS2 was not applied. Details ▾Hide ▴

Rule

TP53 VCEP PS2

Evidence considered

TP53 VCEP de novo point system

Still missing

No documented maternity/paternity-confirmed de novo case was identified.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

PS4 No verified TP53 VCEP point total from affected probands was identified for this variant, so PS4 was not applied. Details ▾Hide ▴

Rule

TP53 VCEP PS4

Evidence considered

TP53 VCEP PS4 point thresholds

Still missing

No exact germline proband count and point-based PS4 calculation were identified.

Sources

cspec ↗vcep_ps4_points_table

PM1 This missense change is not one of the TP53 codons automatically eligible for PM1 under the VCEP specification, and a verified Cancer Hotspots count for the exact p.Leu344Pro substitution was not established from the retrieved evidence. PM1 was therefore not applied. Details ▾Hide ▴

Rule

TP53 VCEP PM1

Evidence considered

TP53 VCEP PM1 codon list and hotspot-count rule
Cancer Hotspots result marked uncertain

Still missing

Exact somatic occurrence count for p.Leu344Pro in Cancer Hotspots remains unverified.

Sources

cspec ↗hotspots ↗

PM5 A different missense change at codon 344 is present in ClinVar, but the retrieved evidence does not verify a qualifying TP53 VCEP pathogenic or clinically qualifying likely pathogenic comparison needed for PM5 application. PM5 was therefore not applied. Details ▾Hide ▴

Rule

TP53 VCEP PM5

Evidence considered

TP53 VCEP PM5 requires prior TP53 VCEP pathogenic/likely pathogenic missense variants at the same residue

Still missing

Need direct confirmation of same-residue TP53 VCEP-classified pathogenic or qualifying likely pathogenic variants.

Sources

cspec ↗clinvar ↗

PP1 No segregation data were identified showing this variant co-segregates with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 was not applied. Details ▾Hide ▴

Rule

TP53 VCEP PP1

Evidence considered

TP53 VCEP segregation thresholds

Still missing

No family segregation data were identified.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

PP4 No case-level blood variant allele fraction or mosaicism data were identified to support TP53 VCEP PP4, so this criterion was not applied. Details ▾Hide ▴

Rule

TP53 VCEP PP4

Evidence considered

TP53 VCEP PP4 requires low-VAF observations in affected individuals

Still missing

No variant allele fraction data from affected individuals were identified.

Sources

cspec ↗

BS2 No evidence was identified showing this variant in the number of unrelated cancer-free older females required for TP53 VCEP BS2, so this criterion was not applied. Details ▾Hide ▴

Rule

TP53 VCEP BS2

Evidence considered

TP53 VCEP BS2 thresholds

Still missing

No qualifying unaffected-carrier dataset was identified.

Sources

cspec ↗

BS4 No lack-of-segregation data were identified in affected family members with Li-Fraumeni syndrome-associated cancers, so BS4 was not applied. Details ▾Hide ▴

Rule

TP53 VCEP BS4

Evidence considered

TP53 VCEP BS4 rule

Still missing

No informative non-segregation family data were identified.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant in the TP53 oligomerization domain and does not fall into the TP53 null-variant or canonical splice categories used for PVS1. Available evidence does not support a predicted loss-of-function mechanism through truncation or canonical splice disruption for this change. Details ▾Hide ▴

Rule

TP53 VCEP PVS1 decision tree

Evidence considered

TP53 VCEP PVS1 framework
generic PVS1 scaffold indicates this variant is outside default null-variant buckets

Still missing

No direct RNA study was identified for this exact variant.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_flowchart

PM3 N/APM3 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks PM3 not applicable

Sources

cspec ↗

PM4 N/APM4 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks PM4 not applicable

Sources

cspec ↗

PM6 N/APM6 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks PM6 not applicable

Sources

cspec ↗

PP2 N/APP2 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks PP2 not applicable

Sources

cspec ↗

BP1 N/ABP1 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks BP1 not applicable

Sources

cspec ↗

BP2 N/ABP2 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks BP2 not applicable

Sources

cspec ↗

BP3 N/ABP3 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks BP3 not applicable

Sources

cspec ↗

BP5 N/ABP5 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks BP5 not applicable

Sources

cspec ↗

BP6 N/ABP6 is not applicable for the TP53 VCEP framework. Details ▾Hide ▴

Rule

Not applicable in TP53 VCEP

Evidence considered

TP53 VCEP marks BP6 not applicable

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splicing impact and is not applicable to this missense variant. Details ▾Hide ▴

Rule

TP53 VCEP BP7

Evidence considered

TP53 VCEP BP7 scope excludes missense variants

Sources

cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.1031T>C
Protein (HGVS p.): NP_000537.3:p.(Leu344Pro)
GRCh38: chr17:7670678 A>G
GRCh37: chr17:7573996 A>G

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 1 / 1,614,076 alleles AF 6.2e-07 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,076 alleles · 0 hom

South Asian1 / 91,074

1.1e-05

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.1955e-07; MAF= 0.00006%, 1/1614076 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09801e-05; MAF= 0.00110%, 1/91074 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 VCEP PP3_Moderate

Evidence considered

PP3-BP4 worksheet row: c.1031T>C | p.Leu344Pro | Class C65 | 0.485604 | PP3_moderate
REVEL 0.862
BayesDel 0.485604

Still missing

A directly captured SpliceAI score was not available in the retrieved text
although the TP53 VCEP pre-assigned code supports PP3 application.

Sources

vcep_pp3_bp4_codesbayesdelrevelcspec ↗

Rule

TP53 VCEP BP4

Evidence considered

PP3-BP4 worksheet pre-assigned PP3_moderate
BayesDel 0.485604
REVEL 0.862

Sources

vcep_pp3_bp4_codesbayesdelrevelcspec ↗

BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splicing impact and is not applicable to this missense variant. Details ▾Hide ▴

Rule

TP53 VCEP BP7

Evidence considered

TP53 VCEP BP7 scope excludes missense variants

Sources

cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.862. BayesDel score = 0.485604.

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 1 / 1,614,076 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

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 has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.862. BayesDel score = 0.485604.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52687285, n = 11 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.