About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.74+11C>T, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 2
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_Supporting threshold of <0.00003 overall allele frequency and supports rarity.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
This intronic variant is outside the canonical +/-1,2 splice positions and lies at +11. SpliceAI predicts no splice impact with a maximum delta score of 0.01, which is at or below the TP53 VCEP BP4 threshold of <=0.1 for silent or intronic variants, supporting BP4.
BP7Supporting
BP7 · supporting
This intronic variant is at c.74+11, which is within the TP53 VCEP BP7 intronic range of +7 to +21 away from the splice junction, and SpliceAI predicts no impact to splicing with a maximum delta score of 0.01. This meets TP53 BP7_Supporting.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) + BP7 supporting (-1) = -1 points, which maps to VUS.
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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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 · 8 not assessed · 13 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.74+11C>T (NP_000537.3:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the TP53 VCEP PM2_Supporting threshold of 0.00003.
SpliceAI predicts no significant splice effect with a maximum delta score of 0.01; for a TP53 intronic variant at +11, this supports BP4_Supporting and BP7_Supporting and does not support PP3 or PVS1.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of <0.00003 overall allele frequency and supports rarity. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: allele frequency <0.00003.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 SupportingThis intronic variant is outside the canonical +/-1,2 splice positions and lies at +11. SpliceAI predicts no splice impact with a maximum delta score of 0.01, which is at or below the TP53 VCEP BP4 threshold of <=0.1 for silent or intronic variants, supporting BP4. Details ▾Hide ▴
Rule
TP53 VCEP BP4_Supporting for silent or intronic variants outside +/-1,2: SpliceAI <=0.1.
Evidence considered
- Intronic position +11.
- SpliceAI max delta score is 0.01.
Sources
BP7 SupportingThis intronic variant is at c.74+11, which is within the TP53 VCEP BP7 intronic range of +7 to +21 away from the splice junction, and SpliceAI predicts no impact to splicing with a maximum delta score of 0.01. This meets TP53 BP7_Supporting. Details ▾Hide ▴
Rule
TP53 VCEP BP7_Supporting: intronic variant at or beyond +7 to -21 with SpliceAI <=0.1 and no predicted splice impact.
Evidence considered
- Intronic position +11.
- SpliceAI max delta score is 0.01.
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This intronic variant is at c.74+11, outside the canonical +/-1,2 splice positions and outside the default null-variant categories used for PVS1. SpliceAI predicts no meaningful splice effect (max delta score 0.01), and no TP53 RNA-based PVS1 assignment was identified for this variant, so available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 requires applicable null/splice evidence; this c.74+11 intronic variant does not meet that threshold on current evidence.
Evidence considered
- TP53 VCEP PVS1 framework is available for TP53.
- Variant is intronic at +11 rather than a canonical splice-site or other default null category.
- SpliceAI max delta score is 0.01.
Still missing
- No RNA study or other direct transcript evidence was identified for this exact variant.
- No demonstrated abnormal transcript consequence was identified.
Sources
cspec ↗spliceai ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_flowchartvcep_pvs1_splicing_worksheet
PP3 This intronic +11 variant does not meet the TP53 VCEP PP3 splice threshold. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the PP3 threshold of >=0.2. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for intronic splice variants outside +/-1,2 requires SpliceAI >=0.2.
Evidence considered
- Intronic variant at +11 position.
- SpliceAI max delta score is 0.01.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the TP53 BA1 stand-alone benign threshold of filtering allele frequency >=0.001. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency >=0.001.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the TP53 BS1 threshold of filtering allele frequency >=0.0003. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency >=0.0003 and <0.001.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with the phenotype and parental testing details required for TP53 PS2 assessment was identified. Details ▾Hide ▴
Rule
TP53 VCEP PS2 is point-based from confirmed de novo observations.
Evidence considered
- No de novo evidence was present in the reviewed materials.
Still missing
- No parental testing data were identified.
- No de novo case report with TP53-relevant phenotype details was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3 No functional study was identified showing that this exact intronic variant causes an abnormal TP53 transcript or other validated damaging functional effect. The TP53 VCEP protein-function worksheets are directed to missense and small in-frame deletion variants and do not provide a direct PS3 assignment for this variant. Details ▾Hide ▴
Rule
TP53 VCEP PS3 uses eligible functional assay evidence; none was identified for this variant.
Evidence considered
- No variant-specific functional evidence was identified.
- TP53 functional worksheet review did not identify this intronic variant.
Still missing
- No RNA study
- minigene assay
- or other variant-specific functional assay was identified.
Sources
PS4 This variant is absent from population databases, which is compatible with the PM2_Supporting prerequisite, but no affected case series or point-based TP53 PS4 evidence was identified. Details ▾Hide ▴
Rule
TP53 VCEP PS4 requires case-based point accumulation after rarity is established.
Evidence considered
- Variant is absent from gnomAD v2.1 and v4.1.
- No case observations were identified.
Still missing
- No unrelated affected probands were identified for PS4 point scoring.
- No TP53-specific PS4 point total could be established.
Sources
PP1 No segregation data were identified, so there is no evidence to support TP53 PP1. Details ▾Hide ▴
Rule
TP53 VCEP PP1 requires 3 or more informative meioses depending on strength.
Evidence considered
- No segregation evidence was present in the reviewed materials.
Still missing
- No pedigree or meiosis count was identified.
- No affected carrier segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction data or other TP53-specific clinical observation data were identified to support PP4. Details ▾Hide ▴
Rule
TP53 VCEP PP4 is based on low-VAF clinical observations.
Evidence considered
- No PP4-relevant case observation data were present.
Still missing
- No VAF-based clinical observation data were identified.
- No phenotype-specific TP53 PP4 evidence was identified.
Sources
BS2 No source was identified showing this variant in the number of unrelated older females without cancer required for TP53 BS2. Details ▾Hide ▴
Rule
TP53 VCEP BS2 is based on unaffected older female carriers from a single source.
Evidence considered
- No BS2-relevant unaffected carrier evidence was identified.
Still missing
- No single-source unaffected carrier series was identified.
Sources
BS3 No RNA or other functional study was identified showing that this exact variant has no effect on TP53 splicing or function, so BS3 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires qualifying functional evidence showing no damaging effect.
Evidence considered
- No variant-specific benign functional evidence was identified.
Still missing
- No negative splicing assay or other benign functional study was identified.
Sources
BS4 No lack-of-segregation evidence was identified in affected relatives with TP53-associated cancers, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires lack of segregation in affected family members.
Evidence considered
- No BS4-relevant family data were identified.
Still missing
- No pedigree with informative non-segregation was identified.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is a same-amino-acid-change rule for variants with an established protein substitution. This intronic variant has no defined amino acid substitution, so PS1 is not applicable. Details ▾Hide ▴
Rule
TP53 VCEP PS1 applies to amino acid substitutions previously classified by the TP53 VCEP.
Evidence considered
- Predicted protein consequence is p.?.
- Variant is intronic rather than missense.
Sources
PM1 N/APM1 in the TP53 VCEP framework is directed to missense variants at hotspot codons or recurrent somatic amino acid changes. This intronic variant does not create a defined amino acid substitution, so PM1 is not applicable. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to hotspot missense changes.
Evidence considered
- Variant is intronic with protein consequence p.?.
Sources
PM3 VCEPPM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM3 as not applicable.
Sources
PM4 VCEPPM4 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM4 as not applicable.
Sources
PM5 N/APM5 in the TP53 VCEP framework is a same-residue missense rule. This intronic variant is not missense-like and has no amino acid residue context for comparator review, so PM5 is not applicable. Details ▾Hide ▴
Rule
TP53 VCEP PM5 applies only to missense variants with qualifying same-residue TP53 comparators.
Evidence considered
- PM5 candidate review found the variant is not eligible for classic same-residue missense PM5.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM6 as not applicable.
Sources
PP2 VCEPPP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP2 as not applicable.
Sources
PP5 VCEPPP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP5 as not applicable.
Sources
BP1 VCEPBP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP1 as not applicable.
Sources
BP2 VCEPBP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP2 as not applicable.
Sources
BP3 VCEPBP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP3 as not applicable.
Sources
BP5 VCEPBP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP5 as not applicable.
Sources
BP6 VCEPBP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP6 as not applicable.
Sources
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.74+11C>T
- Protein (HGVS p.)
- NP_000537.3:p.?
- GRCh38
- chr17:7676510 G>A
- GRCh37
- chr17:7579828 G>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
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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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis intronic variant is outside the canonical +/-1,2 splice positions and lies at +11. SpliceAI predicts no splice impact with a maximum delta score of 0.01, which is at or below the TP53 VCEP BP4 threshold of <=0.1 for silent or intronic variants, supporting BP4. Details ▾Hide ▴
Rule
TP53 VCEP BP4_Supporting for silent or intronic variants outside +/-1,2: SpliceAI <=0.1.
Evidence considered
- Intronic position +11.
- SpliceAI max delta score is 0.01.
Sources
BP7 SupportingThis intronic variant is at c.74+11, which is within the TP53 VCEP BP7 intronic range of +7 to +21 away from the splice junction, and SpliceAI predicts no impact to splicing with a maximum delta score of 0.01. This meets TP53 BP7_Supporting. Details ▾Hide ▴
Rule
TP53 VCEP BP7_Supporting: intronic variant at or beyond +7 to -21 with SpliceAI <=0.1 and no predicted splice impact.
Evidence considered
- Intronic position +11.
- SpliceAI max delta score is 0.01.
Sources
PP3 This intronic +11 variant does not meet the TP53 VCEP PP3 splice threshold. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the PP3 threshold of >=0.2. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for intronic splice variants outside +/-1,2 requires SpliceAI >=0.2.
Evidence considered
- Intronic variant at +11 position.
- SpliceAI max delta score is 0.01.
Sources
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC 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/?term=NM_000546.5%3Ac.74%2B11C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579828-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7676510-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.74%2…
- OncoKB ↗www.oncokb.org/gene/TP53/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.74+11C%3ET
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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).