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TP53c.743G>TPathogenic
Print report
Variant interpretation report

TP53 c.743G>T, p.(Arg248Leu)

NM_000546.5:c.743G>T NP_000537.3:p.(Arg248Leu) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A 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.

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: 5 Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong

In the TP53 functional worksheet, p.Arg248Leu is pre-assigned PS3. The compiled eligible assay results show this variant was non-functional in the Kato transactivation dataset and showed loss of function in the other eligible functional assays summarized for TP53, supporting a damaging effect on protein function.

PM1Moderate
PM1 · moderate

This missense variant affects TP53 codon 248, one of the codons explicitly specified by the TP53 VCEP for PM1 at moderate strength. The same amino acid change has also been observed 161 times in COSMIC, consistent with recurrence at this hotspot residue.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the ancestry-group threshold of less than 0.00004 when multiple alleles are present.

PP3Moderate
PP3 · moderate

In the TP53 VCEP bioinformatic worksheet, NM_000546.5:c.743G>T (p.Arg248Leu) is pre-assigned PP3_moderate. The entry shows Align-GVGD class C65 and BayesDel 0.570318, which is above the TP53 VCEP PP3_Moderate threshold of 0.16, and SpliceAI predicts no meaningful splice effect (max delta score 0.01). REVEL is also high at 0.96, which is consistent with a damaging missense effect.

PP5Supporting
PP5 · supporting

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM1 moderate (+2) + PM2 supporting (+1) + PP3 moderate (+2) + PP5 supporting (+1) = 10 points, which maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

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 →
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely 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: 5 met · 4 not met · 8 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The TP53 c.743G>T (p.Arg248Leu) variant has been observed in somatic cancers in COSMIC 161 times and has been reported in ClinVar with an expert panel pathogenic classification.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the TP53 VCEP PM2_Supporting threshold.

In the TP53 VCEP functional worksheet, p.Arg248Leu is summarized as non-functional with loss-of-function results across eligible assays and is pre-assigned PS3, supporting a damaging effect on p53 function.

In the TP53 VCEP bioinformatic worksheet, this missense change is pre-assigned PP3_moderate with Align-GVGD class C65 and BayesDel 0.570318, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.01; REVEL is also high at 0.96.

Met · 5

PS3 StrongIn the TP53 functional worksheet, p.Arg248Leu is pre-assigned PS3. The compiled eligible assay results show this variant was non-functional in the Kato transactivation dataset and showed loss of function in the other eligible functional assays summarized for TP53, supporting a damaging effect on protein function. Details ▾Hide ▴
Rule
TP53 VCEP PS3 Strong
Evidence considered
  • Functional worksheet row: R248L -> Non-functional / LOF / LOF / LOF -> PS3
  • TP53 VCEP functional flowchart for PS3/BS3 interpretation
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗
PM1 ModerateThis missense variant affects TP53 codon 248, one of the codons explicitly specified by the TP53 VCEP for PM1 at moderate strength. The same amino acid change has also been observed 161 times in COSMIC, consistent with recurrence at this hotspot residue. Details ▾Hide ▴
Rule
TP53 VCEP PM1 Moderate for codon 248 missense variants
Evidence considered
  • TP53 VCEP PM1 codon list includes codon 248
  • COSMIC somatic count 161 for this amino acid change
Sources
cspec ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the ancestry-group threshold of less than 0.00004 when multiple alleles are present. Details ▾Hide ▴
Rule
TP53 VCEP PM2 Supporting
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • TP53 VCEP PM2 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
PP3 ModerateIn the TP53 VCEP bioinformatic worksheet, NM_000546.5:c.743G>T (p.Arg248Leu) is pre-assigned PP3_moderate. The entry shows Align-GVGD class C65 and BayesDel 0.570318, which is above the TP53 VCEP PP3_Moderate threshold of 0.16, and SpliceAI predicts no meaningful splice effect (max delta score 0.01). REVEL is also high at 0.96, which is consistent with a damaging missense effect. Details ▾Hide ▴
Rule
TP53 VCEP PP3 Moderate
Evidence considered
  • PP3-BP4 worksheet row: c.743G>T p.Arg248Leu -> Class C65
  • BayesDel 0.570318
  • PP3_moderate
  • SpliceAI 0.01
  • REVEL score 0.96
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
PP5 SupportingExpert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Rule
TP53 VCEP PP5 not applicable
Evidence considered
  • TP53 VCEP marks PP5 not applicable
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BA1 threshold of filtering allele frequency at or above 0.001. Details ▾Hide ▴
Rule
TP53 VCEP BA1
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • TP53 VCEP BA1 threshold 0.001
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BS1 threshold of filtering allele frequency at or above 0.0003 and below 0.001. Details ▾Hide ▴
Rule
TP53 VCEP BS1
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • TP53 VCEP BS1 threshold 0.0003 to <0.001
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS3 Available functional evidence does not support retained or near-normal TP53 function. Instead, the TP53 functional worksheet summarizes non-functional and loss-of-function results for p.Arg248Leu, which argues against BS3. Details ▾Hide ▴
Rule
TP53 VCEP BS3
Evidence considered
  • Functional worksheet row for R248L is pre-assigned PS3
  • not BS3
  • Assay summary shows non-functional/LOF results
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗
BP4 Available computational evidence does not support a benign missense effect. In the TP53 VCEP bioinformatic worksheet, this variant is assigned PP3_moderate rather than BP4; BayesDel is 0.570318, which is above the damaging threshold of 0.16, while SpliceAI shows no meaningful splice effect (max delta score 0.01). Details ▾Hide ▴
Rule
TP53 VCEP BP4
Evidence considered
  • PP3-BP4 worksheet row assigns PP3_moderate
  • BayesDel 0.570318
  • SpliceAI max delta score 0.01
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗

Not assessed · 8 · no assessment recorded

PS1 No alternate nucleotide change producing the same TP53 p.Arg248Leu amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic assertion was identified in the reviewed evidence. Details ▾Hide ▴
Rule
TP53 VCEP PS1
Evidence considered
  • ClinVar record for the current nucleotide change
  • TP53 VCEP PS1 rule requires a previously classified same-amino-acid substitution
Still missing
  • Need a documented alternate nucleotide substitution encoding p.Arg248Leu with a TP53 VCEP pathogenic or likely pathogenic classification.
Sources
clinvar ↗cspec ↗
PS2 No confirmed de novo observation with maternity and paternity assessment and the phenotype details required for TP53 point-based scoring was identified. Details ▾Hide ▴
Rule
TP53 VCEP PS2 point-based framework
Evidence considered
  • No de novo case details were present in the reviewed evidence
  • TP53 VCEP PS2 uses point-based scoring by proband cancer type
Still missing
  • Need confirmed de novo case data with relationship testing and Li-Fraumeni syndrome cancer point assignment.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 This variant meets PM2_Supporting as a population prerequisite for TP53 PS4, but no germline proband-level Li-Fraumeni syndrome cancer observations with enough information to assign TP53 PS4 points were identified. Details ▾Hide ▴
Rule
TP53 VCEP PS4 point-based framework
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
  • No PS4 point-scored germline case series were identified in the reviewed evidence
Still missing
  • Need exact germline proband observations and TP53 PS4 point totals.
Sources
cspec ↗vcep_ps4_points_tablegnomad_v2 ↗gnomad_v4 ↗
PM5 The reviewed evidence confirms that this variant affects codon 248, but it does not document the number of different TP53 VCEP-classified pathogenic or likely pathogenic missense variants already established at this same residue for direct PM5 scoring. Details ▾Hide ▴
Rule
TP53 VCEP PM5
Evidence considered
  • Variant affects TP53 residue Arg248
  • TP53 VCEP PM5 requires previously classified missense variants at the same residue
Still missing
  • Need exact same-residue TP53 VCEP pathogenic or likely pathogenic comparator variants and their count.
Sources
cspec ↗clinvar ↗
PP1 No segregation data with informative meioses across one or more families were identified for this variant. Details ▾Hide ▴
Rule
TP53 VCEP PP1
Evidence considered
  • No family segregation evidence was present in the reviewed materials
  • TP53 VCEP PP1 uses meiosis-count thresholds
Still missing
  • Need family segregation data with informative meiosis counts and Li-Fraumeni syndrome cancer phenotypes.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction data or phenotype observations meeting the TP53 VCEP PP4 low-level mosaicism framework were identified. Details ▾Hide ▴
Rule
TP53 VCEP PP4
Evidence considered
  • No PP4-eligible low-VAF clinical observations were documented
Still missing
  • Need variant allele fraction data and clinical context for one or more qualifying observations.
Sources
cspec ↗
BS2 No single-source dataset showing unrelated females age 60 years or older without cancer who carry this variant was identified. Details ▾Hide ▴
Rule
TP53 VCEP BS2
Evidence considered
  • No BS2 carrier dataset was present in the reviewed evidence
Still missing
  • Need qualifying unaffected carrier observations from a single source.
Sources
cspec ↗
BS4 No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified. Details ▾Hide ▴
Rule
TP53 VCEP BS4
Evidence considered
  • No family non-segregation evidence was present in the reviewed materials
Still missing
  • Need informative non-segregation data in affected relatives.
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 variant is a missense substitution, not a nonsense, frameshift, canonical +/-1,2 splice, or other TP53 null variant type eligible for PVS1. SpliceAI also predicts no meaningful splice disruption (max delta score 0.01). Details ▾Hide ▴
Rule
TP53 VCEP/ClinGen PVS1 framework for null variants only
Evidence considered
  • Generic PVS1 scaffold categorized the variant outside null-variant buckets
  • TP53 PVS1 flowchart applies to null and splice-disrupting variant classes
  • SpliceAI max delta score 0.01
Sources
pvs1_variant_assessmentvcep_pvs1_flowchartspliceai ↗
PM3 N/APM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP PM3 not applicable
Evidence considered
  • TP53 VCEP marks PM3 not applicable
Sources
cspec ↗
PM4 N/APM4 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP PM4 not applicable
Evidence considered
  • TP53 VCEP marks PM4 not applicable
Sources
cspec ↗
PM6 N/APM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP PM6 not applicable
Evidence considered
  • TP53 VCEP marks PM6 not applicable
Sources
cspec ↗
PP2 N/APP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP PP2 not applicable
Evidence considered
  • TP53 VCEP marks PP2 not applicable
Sources
cspec ↗
BP1 N/ABP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP BP1 not applicable
Evidence considered
  • TP53 VCEP marks BP1 not applicable
Sources
cspec ↗
BP2 N/ABP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP BP2 not applicable
Evidence considered
  • TP53 VCEP marks BP2 not applicable
Sources
cspec ↗
BP3 N/ABP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP BP3 not applicable
Evidence considered
  • TP53 VCEP marks BP3 not applicable
Sources
cspec ↗
BP5 N/ABP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP BP5 not applicable
Evidence considered
  • TP53 VCEP marks BP5 not applicable
Sources
cspec ↗
BP6 N/ABP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP BP6 not applicable
Evidence considered
  • TP53 VCEP marks BP6 not applicable
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous and certain intronic variants, whereas this variant is missense. Details ▾Hide ▴
Rule
TP53 VCEP BP7
Evidence considered
  • Missense variant class
  • TP53 BP7 framework is for synonymous/intronic 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.743G>T
Protein (HGVS p.)
NP_000537.3:p.(Arg248Leu)
GRCh38
chr17:7674220 C>A
GRCh37
chr17:7577538 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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 ModerateIn the TP53 VCEP bioinformatic worksheet, NM_000546.5:c.743G>T (p.Arg248Leu) is pre-assigned PP3_moderate. The entry shows Align-GVGD class C65 and BayesDel 0.570318, which is above the TP53 VCEP PP3_Moderate threshold of 0.16, and SpliceAI predicts no meaningful splice effect (max delta score 0.01). REVEL is also high at 0.96, which is consistent with a damaging missense effect. Details ▾Hide ▴
Rule
TP53 VCEP PP3 Moderate
Evidence considered
  • PP3-BP4 worksheet row: c.743G>T p.Arg248Leu -> Class C65
  • BayesDel 0.570318
  • PP3_moderate
  • SpliceAI 0.01
  • REVEL score 0.96
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
BP4 Available computational evidence does not support a benign missense effect. In the TP53 VCEP bioinformatic worksheet, this variant is assigned PP3_moderate rather than BP4; BayesDel is 0.570318, which is above the damaging threshold of 0.16, while SpliceAI shows no meaningful splice effect (max delta score 0.01). Details ▾Hide ▴
Rule
TP53 VCEP BP4
Evidence considered
  • PP3-BP4 worksheet row assigns PP3_moderate
  • BayesDel 0.570318
  • SpliceAI max delta score 0.01
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous and certain intronic variants, whereas this variant is missense. Details ▾Hide ▴
Rule
TP53 VCEP BP7
Evidence considered
  • Missense variant class
  • TP53 BP7 framework is for synonymous/intronic 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 = 0.01). REVEL score = 0.96. BayesDel score = 0.570318.

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 Captured gnomAD v4.1 source record 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as 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 = 0.01). REVEL score = 0.96. BayesDel score = 0.570318.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely 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; COSV52675468, n = 161 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.