About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.1123C>A, p.(Gln375Lys)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and supports PM2 at supporting strength.
Benign criteria applied · 1
BS3Strong
BS3 · strong
In the TP53 VCEP functional worksheet, p.(Gln375Lys) is listed as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code. These results support retained TP53 function and argue against a damaging effect.
Recorded classification: Likely benign
TP53 VCEP v2.4.0 Tavtigian point-based final-classification framework from CSPEC/VCEP. Applied points: BS3_Strong = -4 and PM2_Supporting = +1, for a net score of -3; Likely Benign corresponds to -6 to -2.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie 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: 2 met · 5 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 c.1123C>A (p.Gln375Lys) variant has been observed in somatic cancers in COSMIC (4 occurrences) and has been reported in ClinVar as Likely benign by a single clinical laboratory.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports TP53 PM2 at supporting strength and does not support BA1 or BS1.
In the TP53 VCEP functional worksheet, p.(Gln375Lys) is classified as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code, supporting retained TP53 function.
Computational evidence is mixed: REVEL is 0.339 and BayesDel is -0.143957, the TP53 PP3/BP4 worksheet preliminarily lists BP4_moderate for c.1123C>A, but that worksheet also flags possible splice impact while the case-specific SpliceAI lookup reported a max delta score of 0.00, so PP3 and BP4 were not applied pending review of the discordant splice predictions.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and supports PM2 at supporting strength. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting for variants with allele frequency <0.00003 in large population datasets.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- TP53 PM2 threshold: AF < 0.00003
Sources
BS3 StrongIn the TP53 VCEP functional worksheet, p.(Gln375Lys) is listed as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code. These results support retained TP53 function and argue against a damaging effect. Details ▾Hide ▴
Rule
TP53 VCEP BS3_Strong for functional Kato data and no loss of function by the majority of eligible assays.
Evidence considered
- Functional worksheet row: Q375K | Functional | noLOF | BS3
- TP53 VCEP BS3 applies when Kato data are functional and the majority of eligible assays do not show LOF
Sources
cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes1282660930224644397743252997996516007150
Not met · 5 · evaluated, threshold not reached
PS3 Available TP53 functional evidence does not support a damaging loss-of-function effect for this variant. The TP53 functional worksheet lists p.(Gln375Lys) as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned benign functional code rather than PS3. Details ▾Hide ▴
Rule
TP53 VCEP PS3 requires non-functional or partially functional results with loss of function across eligible assays.
Evidence considered
- Functional worksheet row: Q375K | Functional | noLOF | BS3
- TP53 VCEP PS3 requires non-functional/LOF results across eligible assays
Sources
cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes1282660930224644397743252997996516007150
PS4 Although the variant is absent from gnomAD and therefore meets the population prerequisite for TP53 PS4 review, no qualifying proband observations or Li-Fraumeni syndrome point total were identified to support PS4. Details ▾Hide ▴
Rule
TP53 VCEP PS4 is point based and should be considered only after PM2_Supporting is met.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- No PS4 case evidence identified
Still missing
- No qualifying affected proband observations
- No PS4 point total
Sources
PM1 This missense variant has been reported 4 times in COSMIC, but no Cancer Hotspots residue row or statistically significant hotspot evidence was identified for codon 375. Available evidence therefore does not support TP53 PM1. Details ▾Hide ▴
Rule
TP53 VCEP PM1 uses specific hotspot codons or Cancer Hotspots recurrence thresholds.
Evidence considered
- COSMIC somatic count 4
- No hotspot row found for TP53 Q375
Still missing
- Cancer Hotspots review was marked uncertain and may benefit from manual confirmation.
Sources
BA1 This variant is absent from gnomAD and does not reach the TP53 BA1 filtering allele frequency threshold of 0.001. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency ≥0.001 in an eligible ancestry group.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- TP53 BA1 threshold: FAF ≥ 0.001
Sources
BS1 This variant is absent from gnomAD and does not reach the TP53 BS1 filtering allele frequency threshold of 0.0003. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency ≥0.0003 in an eligible ancestry group.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- TP53 BS1 threshold: FAF ≥ 0.0003
Sources
Not assessed · 9 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a different TP53 variant already classified as pathogenic or likely pathogenic under TP53 VCEP specifications. Details ▾Hide ▴
Rule
TP53 VCEP PS1 uses previously classified TP53 pathogenic or likely pathogenic same-amino-acid variants.
Evidence considered
- TP53 VCEP PS1 requires a previously classified TP53 variant with the same amino acid change
Still missing
- No verified TP53 VCEP pathogenic or likely pathogenic same-amino-acid comparator was identified in the available evidence.
Sources
PS2 No de novo observations, parental testing results, or phenotype point assignments were identified for this variant, so PS2 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PS2 requires qualifying de novo observations scored by LFS cancer points.
Evidence considered
- Available evidence contained no de novo case data
- TP53 VCEP PS2 is point based
Still missing
- No confirmed de novo case
- No maternity/paternity confirmation
- No proband point total for TP53 PS2 scoring
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PM5 This is a missense variant at codon 375, and TP53 uses classic same-residue PM5 logic. However, no verified TP53 VCEP pathogenic or likely pathogenic same-residue comparator variants were identified in the available evidence, so PM5 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PM5 requires previously classified TP53 missense variants at the same residue.
Evidence considered
- Variant consequence is p.(Gln375Lys)
- pm5_candidates did not provide verified eligible comparators
Still missing
- No verified same-residue TP53 VCEP pathogenic or likely pathogenic comparator was available for review.
Sources
cspec ↗pm5_candidates
PP1 No segregation data, meiosis counts, or multiple affected family observations were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PP1 is based on the number of informative cosegregations.
Evidence considered
- No family segregation evidence identified
- TP53 PP1 requires 3 or more informative meioses
Still missing
- No cosegregation evidence
- No informative pedigree data
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP3 Available computational evidence does not support confident PP3 application. REVEL is 0.339 and local BayesDel is -0.143957, while the TP53 PP3/BP4 worksheet lists c.1123C>A with a preliminary BP4_moderate assignment but flags possible splice-related reconsideration based on a worksheet SpliceAI value of 0.49; in contrast, the case-specific SpliceAI lookup reported a max delta score of 0.00. Because the splicing predictions are discordant, PP3 is not applied. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying damaging computational evidence or predicted splice impact under the TP53 flowchart.
Evidence considered
- REVEL 0.339
- BayesDel -0.143957
- Case-specific SpliceAI max delta 0.00
- TP53 PP3/BP4 worksheet row for c.1123C>A lists BP4_moderate and SpliceAI 0.49 with note to consider PP3 for splicing
Still missing
- Manual resolution of the discrepancy between the TP53 worksheet SpliceAI value and the case-specific SpliceAI lookup.
Sources
revelbayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
PP4 No low-variant-allele-fraction blood finding, constitutional mosaicism evidence, or other TP53-specific PP4 qualifying observation was identified, so PP4 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PP4 uses qualifying low-VAF blood observations suggestive of constitutional mosaicism.
Evidence considered
- TP53 PP4 is based on qualifying low-VAF observations
Still missing
- No VAF-based observation data
Sources
BS2 No source identified 2 or more unrelated older female carriers without cancer, so BS2 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS2 requires unaffected older female carriers from a single source.
Evidence considered
- No unaffected carrier dataset identified
Still missing
- No qualifying unaffected carrier series from a single source
Sources
BS4 No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires lack of segregation in affected relatives with LFS-associated cancers.
Evidence considered
- No family non-segregation evidence identified
Still missing
- No informative non-segregation data
Sources
BP4 Computational evidence suggests a benign missense effect by BayesDel (-0.143957), and the TP53 PP3/BP4 worksheet preliminarily assigns BP4_moderate for c.1123C>A. However, that same worksheet records a SpliceAI value of 0.49 and advises reconsideration for possible splice impact, while the case-specific SpliceAI lookup reported a max delta score of 0.00. Because TP53 BP4 requires confidence that no splice effect is predicted, BP4 is not applied until this discrepancy is resolved. Details ▾Hide ▴
Rule
TP53 VCEP BP4 for missense variants requires benign computational evidence and no predicted splice impact.
Evidence considered
- BayesDel -0.143957
- REVEL 0.339
- Case-specific SpliceAI max delta 0.00
- TP53 PP3/BP4 worksheet row for c.1123C>A: BP4_moderate with worksheet SpliceAI 0.49
Still missing
- Manual review of the discrepant splice predictions is needed before applying BP4.
Sources
bayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗revel
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, TP53 p.(Gln375Lys), and does not create a nonsense, frameshift, canonical ±1/2 splice, or other null-variant scenario eligible for TP53 PVS1 application. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 flowchart for null variants; missense variants are not eligible absent a proven qualifying splicing/null mechanism.
Evidence considered
- NM_000546.6:c.1123C>A maps to NP_000537.3:p.(Gln375Lys)
- pvs1_variant_assessment states the variant is not in a default null-variant bucket
- TP53 VCEP reserves PVS1 for null/splice mechanisms
Sources
PM3 N/APM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM3 not applicable
Sources
PM4 N/APM4 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM4 not applicable
Sources
PM6 N/APM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM6 not applicable
Sources
PP2 N/APP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP2 not applicable
Sources
PP5 N/APP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP5 not applicable
Sources
BP1 N/ABP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP1 not applicable
Sources
BP2 N/ABP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP2 not applicable
Sources
BP3 N/ABP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP3 not applicable
Sources
BP5 N/ABP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP5 not applicable
Sources
BP6 N/ABP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP6 not applicable
Sources
BP7 N/ABP7 is a synonymous or intronic splice-prediction criterion and does not apply to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or eligible intronic variants, not missense substitutions.
Evidence considered
- Variant consequence is missense
- p.(Gln375Lys)
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.1123C>A
- Protein (HGVS p.)
- NP_000537.3:p.(Gln375Lys)
- GRCh38
- chr17:7669668 G>T
- GRCh37
- chr17:7572986 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
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 Available computational evidence does not support confident PP3 application. REVEL is 0.339 and local BayesDel is -0.143957, while the TP53 PP3/BP4 worksheet lists c.1123C>A with a preliminary BP4_moderate assignment but flags possible splice-related reconsideration based on a worksheet SpliceAI value of 0.49; in contrast, the case-specific SpliceAI lookup reported a max delta score of 0.00. Because the splicing predictions are discordant, PP3 is not applied. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying damaging computational evidence or predicted splice impact under the TP53 flowchart.
Evidence considered
- REVEL 0.339
- BayesDel -0.143957
- Case-specific SpliceAI max delta 0.00
- TP53 PP3/BP4 worksheet row for c.1123C>A lists BP4_moderate and SpliceAI 0.49 with note to consider PP3 for splicing
Still missing
- Manual resolution of the discrepancy between the TP53 worksheet SpliceAI value and the case-specific SpliceAI lookup.
Sources
revelbayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
BP4 Computational evidence suggests a benign missense effect by BayesDel (-0.143957), and the TP53 PP3/BP4 worksheet preliminarily assigns BP4_moderate for c.1123C>A. However, that same worksheet records a SpliceAI value of 0.49 and advises reconsideration for possible splice impact, while the case-specific SpliceAI lookup reported a max delta score of 0.00. Because TP53 BP4 requires confidence that no splice effect is predicted, BP4 is not applied until this discrepancy is resolved. Details ▾Hide ▴
Rule
TP53 VCEP BP4 for missense variants requires benign computational evidence and no predicted splice impact.
Evidence considered
- BayesDel -0.143957
- REVEL 0.339
- Case-specific SpliceAI max delta 0.00
- TP53 PP3/BP4 worksheet row for c.1123C>A: BP4_moderate with worksheet SpliceAI 0.49
Still missing
- Manual review of the discrepant splice predictions is needed before applying BP4.
Sources
bayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗revel
BP7 N/ABP7 is a synonymous or intronic splice-prediction criterion and does not apply to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or eligible intronic variants, not missense substitutions.
Evidence considered
- Variant consequence is missense
- p.(Gln375Lys)
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 = 0.339. BayesDel score = -0.143957.
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1798385/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7572986-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7669668-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.1123…
- OncoKB ↗www.oncokb.org/gene/TP53/Q375K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104611511
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.339. BayesDel score = -0.143957.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52716070, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.