About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.-29+100dup, 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 present at an extremely low allele frequency in gnomAD v4.1 (total AF=2.26×10⁻⁵, 9/398,376 alleles), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003. The highest subpopulation frequency is in European (non-Finnish) at AF=3.98×10⁻⁵ (9/226,136 alleles), which is below the subpopulation threshold of 0.00004.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
NM_000546.6:c.-29+100dup is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP PP3/BP4/BP7 flowchart, intronic variants with SpliceAI ≤ 0.1 qualify for BP4_Supporting. SpliceAI max delta score for this variant is 0.00, satisfying this threshold.
BP7Supporting
BP7 · supporting
NM_000546.6:c.-29+100dup is an intronic variant at position +100 of intron 1, which is beyond the +7 position. Per the TP53 VCEP BP7 rule, intronic variants at or beyond +7 to −21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1) qualify for BP7_Supporting. SpliceAI max delta score is 0.00, satisfying this criterion.
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 benign (-1) + BP7 supporting benign (-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
9 / 398,376 alleles
gnomAD v4.1: 9 / 398,376 alleles. Recorded AF 2.25917e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 1/31390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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 · 3 not met · 6 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000546.6:c.-29+100dup is an intronic duplication at position +100 of intron 1 in TP53. SpliceAI predicts no splicing impact (max delta score = 0.00).
The variant is present in gnomAD v4.1 at an extremely low frequency (AF=2.26×10⁻⁵, 9/398,376 alleles; grpmax FAF=2.07×10⁻⁵), meeting PM2_Supporting per TP53 VCEP thresholds (total AF < 0.00003; subpopulation AF < 0.00004).
As an intronic variant outside the core splice motif with SpliceAI score ≤ 0.1, BP4_Supporting is met per the TP53 VCEP PP3/BP4/BP7 flowchart.
As an intronic variant at position +100 (beyond +7) with SpliceAI predicting no splice impact, BP7_Supporting is met per the TP53 VCEP specification (Walker et al. 2023, PMID:37352859).
The variant is absent from ClinVar and COSMIC and has not been reported in the literature. No proband, segregation, de novo, or functional data are available.
All other ACMG/AMP criteria are either not applicable (intronic variant outside scope of VCEP rules for missense/null/functional criteria) or not assessed due to absence of clinical data.
No criteria match.
Met · 3
PM2 SupportingThis variant is present at an extremely low allele frequency in gnomAD v4.1 (total AF=2.26×10⁻⁵, 9/398,376 alleles), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003. The highest subpopulation frequency is in European (non-Finnish) at AF=3.98×10⁻⁵ (9/226,136 alleles), which is below the subpopulation threshold of 0.00004. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF=2.26×10⁻⁵ (9/398
- 376 alleles)
- European (non-Finnish) AF=3.98×10⁻⁵ (9/226
- 136 alleles)
- grpmax FAF=2.07×10⁻⁵.
Still missing
- VAF/allele balance data not reviewed
- gnomAD v2.1 total AF=3.19×10⁻⁵ slightly exceeds the 3.0×10⁻⁵ threshold
- but v4.1 is the most recent version per VCEP guidance.
Sources
BP4 SupportingNM_000546.6:c.-29+100dup is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP PP3/BP4/BP7 flowchart, intronic variants with SpliceAI ≤ 0.1 qualify for BP4_Supporting. SpliceAI max delta score for this variant is 0.00, satisfying this threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- below BP4 threshold of ≤0.1 for intronic variants outside ±1
- 2. No predicted splicing impact.
Still missing
- No RNA splicing assay data to confirm absence of splice aberration at the experimental level.
Sources
spliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP7 SupportingNM_000546.6:c.-29+100dup is an intronic variant at position +100 of intron 1, which is beyond the +7 position. Per the TP53 VCEP BP7 rule, intronic variants at or beyond +7 to −21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1) qualify for BP7_Supporting. SpliceAI max delta score is 0.00, satisfying this criterion. Details ▾Hide ▴
Evidence considered
- Intronic position +100 (beyond +7)
- SpliceAI max delta = 0.00
- BP4 met
- no predicted splice impact per Walker et al. 2023 (PMID:37352859) recommendations.
Still missing
- No RNA splicing assay data to experimentally confirm absence of splice aberration.
Sources
spliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Not met · 3 · evaluated, threshold not reached
PP3 The TP53 VCEP PP3 rule for intronic variants (excluding ±1,2) requires SpliceAI ≥ 0.2. For NM_000546.6:c.-29+100dup, SpliceAI max delta score is 0.00, which is well below the 0.2 threshold. No predicted splicing impact is present. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- does not meet the VCEP PP3 threshold of ≥0.2 for intronic variants.
Sources
BA1 The TP53 VCEP BA1 threshold requires a filtering allele frequency (FAF) ≥ 0.001 (0.1%) in a gnomAD continental subpopulation (excluding founder populations). The grpmax FAF in gnomAD v4.1 is 2.07×10⁻⁵, far below the BA1 threshold. This variant is too rare to be considered a common benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF=2.07×10⁻⁵
- well below the BA1 threshold of 0.001.
Sources
BS1 The TP53 VCEP BS1 threshold requires FAF ≥ 0.0003 (0.03%) but < 0.001 in a gnomAD subpopulation with ≥2,000 alleles tested and ≥2 alleles present. The highest subpopulation AF in gnomAD v4.1 is European (non-Finnish) at 3.98×10⁻⁵ (0.004%), which is well below the 0.03% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 European (non-Finnish) AF=3.98×10⁻⁵ (9/226
- 136 alleles)
- grpmax FAF=2.07×10⁻⁵
- well below BS1 threshold of 0.0003.
Sources
Not assessed · 6 · no assessment recorded
PS2 No de novo observation data are available for this variant. The TP53 VCEP PS2 rule requires proband points based on confirmed maternity/paternity and LFS-associated cancer types. No such evidence was identified in any source. Details ▾Hide ▴
Still missing
- No de novo proband data available for this variant.
PS4 No proband or case-control data are available for this variant. The TP53 VCEP PS4 rule requires point-based scoring of probands with LFS-associated cancers. No clinical cohort or case-control enrichment data were identified. Details ▾Hide ▴
Still missing
- No proband or case-control datasets available for this variant.
PP1 No co-segregation data are available for this variant. The TP53 VCEP PP1 rule requires observed co-segregation in 3–4 meioses (supporting), 5–6 (moderate), or ≥7 (strong) across families. No family or segregation data were identified. Details ▾Hide ▴
Still missing
- No co-segregation or family data available.
PP4 No phenotype or variant allele fraction (VAF) data are available for this variant. The TP53 VCEP PP4 rule requires observation of the variant with VAF 5–25% (moderate) or 5–35% (supporting). No clinical VAF data were identified. Details ▾Hide ▴
Still missing
- No proband phenotype or VAF data available.
BS2 No data on unaffected elderly females carrying this variant are available. The TP53 VCEP BS2 rule requires ≥2 unrelated females who have reached ≥60 years of age without cancer from a single source. No such observations were identified. Details ▾Hide ▴
Still missing
- No data on cancer-free elderly female carriers.
BS4 No segregation data in affected families are available for this variant. The TP53 VCEP BS4 rule requires lack of segregation in family members diagnosed with LFS-associated cancers. No family data were identified. Details ▾Hide ▴
Still missing
- No family segregation data available.
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000546.6:c.-29+100dup is an intronic duplication at position +100 of intron 1, outside canonical splice sites (±1,2). The TP53 VCEP PVS1 flowchart covers null variants (nonsense, frameshift, canonical splice sites, CNVs) only. This intronic duplication does not fall under any PVS1 null-variant bucket. Details ▾Hide ▴
Evidence considered
- Intronic duplication at +100
- not a null variant
- canonical_splice_consensus=false
- SpliceAI max delta=0.00.
Sources
pvs1_variant_assessment
PS1 N/ANM_000546.6:c.-29+100dup is an intronic duplication that does not alter the amino acid sequence. The TP53 VCEP PS1 rule applies only to variants producing the same amino acid change as an established pathogenic variant. Not applicable to a non-coding intronic variant. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid change (protein consequence: p.?).
PS3 N/AThe TP53 VCEP PS3 functional rule applies only to missense variants and small in-frame deletions assessed via protein function assays (Kato, Giacomelli, Kotler, Funk, Kawaguchi). NM_000546.6:c.-29+100dup is an intronic duplication, not amenable to these protein-level functional assays under the VCEP framework. Details ▾Hide ▴
Evidence considered
- Intronic variant
- VCEP functional rules restricted to missense and small in-frame deletions.
PM1 N/AThe TP53 VCEP PM1 rule applies exclusively to missense variants at codons 175, 245, 248, 249, 273, or 282, or to germline missense variants with ≥2 somatic occurrences at cancerhotspots.org. NM_000546.6:c.-29+100dup is an intronic duplication and does not involve any of these codons. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense variant at any PM1-designated codon.
PM4 VCEPThe TP53 VCEP has designated PM4 as Not Applicable for this gene. The VCEP specifications v2.4.0 state PM4 is not applicable for TP53 variant interpretation. Details ▾Hide ▴
PM5 N/AThe TP53 VCEP PM5 rule applies exclusively to missense variants at an amino acid residue where pathogenic/likely pathogenic variants have been established. NM_000546.6:c.-29+100dup is an intronic duplication with no amino acid change (protein: p.?), and is not eligible for PM5 under the VCEP framework. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid residue to compare
- PM5 requires missense changes at a defined residue.
PM6 VCEPThe TP53 VCEP has designated PM6 as Not Applicable. The VCEP specifications v2.4.0 combine PM6 assessment under the PS2 de novo framework, and PM6 alone is not applied. Details ▾Hide ▴
Evidence considered
- TP53 VCEP explicitly marks PM6 as Not Applicable
- de novo assessment consolidated under PS2.
Sources
PP2 VCEPThe TP53 VCEP has designated PP2 as Not Applicable for this gene. PP2 requires a gene with low benign missense variation where missense variants are a common disease mechanism; the VCEP does not apply this criterion for TP53. Details ▾Hide ▴
PP5 VCEPThe TP53 VCEP has designated PP5 as Not Applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends against the use of this criterion. Details ▾Hide ▴
BS3 N/AThe TP53 VCEP BS3 functional rule applies only to missense variants and small in-frame deletions assessed via protein function assays (Kato, Giacomelli, et al.). NM_000546.6:c.-29+100dup is an intronic duplication and is not amenable to these protein-level functional assays under the VCEP framework. Details ▾Hide ▴
Evidence considered
- Intronic variant
- VCEP functional rules restricted to missense and small in-frame deletions.
BP1 VCEPThe TP53 VCEP has designated BP1 as Not Applicable because truncating variants account for only a portion of disease-causing variants in TP53. Details ▾Hide ▴
BP2 VCEPThe TP53 VCEP has designated BP2 as Not Applicable for this gene. Details ▾Hide ▴
BP3 VCEPThe TP53 VCEP has designated BP3 as Not Applicable. BP3 (in-frame deletion/insertion in a repetitive region without known function) does not apply to TP53 or to this intronic duplication variant. Details ▾Hide ▴
BP5 VCEPThe TP53 VCEP has designated BP5 as Not Applicable. BP5 (variant found in a case with an alternate molecular basis for disease) is not applied under the TP53 VCEP framework. Details ▾Hide ▴
BP6 VCEPThe TP53 VCEP has designated BP6 as Not Applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends against the use of this criterion. Details ▾Hide ▴
PS5 N/APS5 is not a criterion defined in the ClinGen TP53 VCEP Specifications (v2.4.0). The VCEP does not include PS5 among its adjudicated criteria. Details ▾Hide ▴
Evidence considered
- PS5 not present in the TP53 VCEP criteria set.
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.-29+100dup
- Protein (HGVS p.)
- NP_000537.3:p.?
- GRCh38
- chr17:7687276 C>CT
- GRCh37
- chr17:7590594 C>CT
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
9 / 398,376 alleles
AF 2.26e-05 · 0 homozygotes · FAF 2.07e-05
gnomAD v2.1
1 / 31,390 alleles
AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.3e-05 · 9 / 398,376 alleles · 0 hom · FAF 2.1e-05
| European (non-Finnish)9 / 226,136 | 4e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,390 alleles · 0 hom
| African/African American1 / 8,708 | 0.00011 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.25917e-05; MAF= 0.00226%, 9/398376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.97991e-05; MAF= 0.00398%, 9/226136 alleles, homozygotes = 0); grpmax FAF= 2.07e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 1/31390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingNM_000546.6:c.-29+100dup is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP PP3/BP4/BP7 flowchart, intronic variants with SpliceAI ≤ 0.1 qualify for BP4_Supporting. SpliceAI max delta score for this variant is 0.00, satisfying this threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- below BP4 threshold of ≤0.1 for intronic variants outside ±1
- 2. No predicted splicing impact.
Still missing
- No RNA splicing assay data to confirm absence of splice aberration at the experimental level.
Sources
spliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP7 SupportingNM_000546.6:c.-29+100dup is an intronic variant at position +100 of intron 1, which is beyond the +7 position. Per the TP53 VCEP BP7 rule, intronic variants at or beyond +7 to −21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1) qualify for BP7_Supporting. SpliceAI max delta score is 0.00, satisfying this criterion. Details ▾Hide ▴
Evidence considered
- Intronic position +100 (beyond +7)
- SpliceAI max delta = 0.00
- BP4 met
- no predicted splice impact per Walker et al. 2023 (PMID:37352859) recommendations.
Still missing
- No RNA splicing assay data to experimentally confirm absence of splice aberration.
Sources
spliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP3 The TP53 VCEP PP3 rule for intronic variants (excluding ±1,2) requires SpliceAI ≥ 0.2. For NM_000546.6:c.-29+100dup, SpliceAI max delta score is 0.00, which is well below the 0.2 threshold. No predicted splicing impact is present. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- does not meet the VCEP PP3 threshold of ≥0.2 for intronic variants.
Sources
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
9 / 398,376 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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_000546.6%3Ac.-29%2B100dup
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7590594-C-CT?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7687276-C-CT?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7687276-C-CT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.-29%…
- OncoKB ↗www.oncokb.org/gene/TP53/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.-29+100dup
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.25917e-05; MAF= 0.00226%, 9/398376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.97991e-05; MAF= 0.00398%, 9/226136 alleles, homozygotes = 0); grpmax FAF= 2.07e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 1/31390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).