About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.-29+121G>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
NM_000546.6:c.-29+121G>T is absent from gnomAD v2.1 and v4.1 (0 alleles). This meets the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%). Caveat: deep intronic positions may have reduced coverage in exome sequencing data, which may contribute to apparent absence.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
NM_000546.6:c.-29+121G>T is an intronic variant outside ±1,2 splice positions with SpliceAI max delta = 0.00. Per TP53 VCEP BP4 rules, intronic variants outside ±1,2 positions with SpliceAI ≤ 0.1 meet BP4_Supporting.
BP7Supporting
BP7 · supporting
NM_000546.6:c.-29+121G>T is an intronic variant at position +121 (beyond +7 from the splice donor) with SpliceAI max delta = 0.00, predicting no impact on splicing. Per TP53 VCEP BP7_Supporting rule: intronic variants at or beyond +7 to -21 positions with SpliceAI ≤ 0.1 and BP4 met qualify for 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 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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.
29 criteria with recorded statuses: 3 met · 11 not met · 0 not assessed · 15 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+121G>T is a deep intronic substitution in intron 1 of TP53, 121 nucleotides downstream of the exon 1 splice donor (c.-29). This variant falls outside all canonical null-variant categories (PVS1 not applicable) and does not alter the amino acid sequence (PS1, PM1, PM5 not applicable).
The variant is absent from gnomAD v2.1 and v4.1 (0 alleles across >1.6 million individuals). This absence meets the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%). However, caution is warranted as deep intronic regions may have reduced coverage in exome sequencing data.
SpliceAI predicts no splicing impact (max delta score = 0.00). No cryptic splice site creation or disruption is predicted. This supports a benign interpretation through two independent TP53 VCEP criteria: BP4_Supporting (computational evidence, SpliceAI ≤ 0.1 for intronic variants outside ±1,2) and BP7_Supporting (intronic variant at +121, beyond +7, with no predicted splicing aberration).
No functional studies, de novo observations, co-segregation data, case-control studies, or ClinVar submissions have been reported for this variant. It is absent from COSMIC and all TP53 locus-specific databases. Multiple pathogenic criteria (PS2, PS3, PS4, PP1, PP4) and benign criteria (BS1, BS2, BS3, BS4, BA1) cannot be assessed due to complete absence of variant-specific clinical or experimental data.
Under the TP53 VCEP v2.4.0 Tavtigian point-based framework, the applied criteria yield: PM2_Supporting (+1 point), BP4_Supporting (-1 point), BP7_Supporting (-1 point). Total = -1 point, which maps to Uncertain Significance (range -1 to +5). However, the VCEP caveat states that a final point value of -1 may be overridden to Likely Benign when at least 2 benign evidence codes are applied AND PM2_Supporting is the only pathogenic code. Both conditions are met here, resulting in a final classification of Likely Benign.
No criteria match.
Met · 3
PM2 SupportingNM_000546.6:c.-29+121G>T is absent from gnomAD v2.1 and v4.1 (0 alleles). This meets the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%). Caveat: deep intronic positions may have reduced coverage in exome sequencing data, which may contribute to apparent absence. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- gnomAD-Canada (0 alleles).
Still missing
- Deep intronic region (+121) may not be well-captured by exome sequencing
- genome sequencing coverage should be verified.
Sources
BP4 SupportingNM_000546.6:c.-29+121G>T is an intronic variant outside ±1,2 splice positions with SpliceAI max delta = 0.00. Per TP53 VCEP BP4 rules, intronic variants outside ±1,2 positions with SpliceAI ≤ 0.1 meet BP4_Supporting. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (≤ 0.1). Intronic variant outside ±1
- 2 canonical splice positions.
Sources
BP7 SupportingNM_000546.6:c.-29+121G>T is an intronic variant at position +121 (beyond +7 from the splice donor) with SpliceAI max delta = 0.00, predicting no impact on splicing. Per TP53 VCEP BP7_Supporting rule: intronic variants at or beyond +7 to -21 positions with SpliceAI ≤ 0.1 and BP4 met qualify for BP7_Supporting. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.-29+121 (>+7 from splice donor). SpliceAI max delta = 0.00 (≤ 0.1). BP4_Supporting is met.
Sources
Not met · 11 · evaluated, threshold not reached
PS2 No de novo observations of NM_000546.6:c.-29+121G>T have been reported in probands with Li-Fraumeni syndrome or TP53-associated cancers. Variant is absent from ClinVar, published literature, and clinical testing databases. Zero proband points available per TP53 VCEP PS2 scoring table. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar and all searched databases. No de novo reports identified.
Still missing
- No proband-level clinical data available for this deep intronic variant.
Sources
PS3 No functional studies have been performed on NM_000546.6:c.-29+121G>T. The TP53 VCEP functional worksheet (Supplementary Table S3) covers missense amino acid substitutions and in-frame deletions only; this deep intronic variant is outside the scope of eligible functional assays (Kato, Giacomelli, Kotler, Funk, Kawaguchi). No variant-specific functional data exist. Details ▾Hide ▴
Evidence considered
- Deep intronic variant not covered by TP53 VCEP functional assay panel. No functional studies identified in literature.
Still missing
- No minigene splicing assay or RNA analysis available for this variant.
PS4 No observations of NM_000546.6:c.-29+121G>T have been reported in affected individuals. The variant is absent from ClinVar, COSMIC, and gnomAD. No proband data are available to tally points under the TP53 VCEP PS4 cancer scoring table. Zero points = PS4 not met. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- gnomAD v2.1
- gnomAD v4.1
- gnomAD-Canada. No affected individuals identified.
Still missing
- No case-control data or proband observations available.
Sources
PP1 No co-segregation data available for NM_000546.6:c.-29+121G>T. No families with this variant have been reported. Zero meioses observed = PP1 not met per TP53 VCEP thresholds (Supporting requires 3-4 meioses). Details ▾Hide ▴
Evidence considered
- No published segregation studies
- no family data identified.
Still missing
- No pedigree or co-segregation data available.
PP3 For intronic variants outside ±1,2 splice positions, TP53 VCEP PP3_Supporting requires SpliceAI ≥ 0.2. SpliceAI max delta for NM_000546.6:c.-29+121G>T is 0.00, well below the threshold. No predicted splice-altering effect. PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0). Does not meet PP3_Supporting threshold of ≥0.2.
Sources
PP4 No observations of NM_000546.6:c.-29+121G>T with variant allele fraction (VAF) 5-35% have been reported. The variant is absent from all databases. Zero qualifying observations = PP4 not met per TP53 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar and all databases. No proband VAF data available.
Still missing
- No clinical testing data with VAF measurements available.
Sources
BA1 NM_000546.6:c.-29+121G>T is absent from gnomAD (0 alleles in v2.1 and v4.1). BA1 requires filtering allele frequency (FAF) ≥ 0.001 (0.1%) in a continental subpopulation. Frequency of 0 is well below this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (0 alleles). FAF effectively 0
- does not meet BA1 threshold of ≥0.001.
Sources
BS1 NM_000546.6:c.-29+121G>T is absent from gnomAD (0 alleles). BS1 requires FAF ≥ 0.0003 (0.03%) but < 0.001 in a continental subpopulation. Frequency of 0 does not meet the lower bound. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (0 alleles). AF effectively 0
- does not meet BS1 threshold of ≥0.0003.
Sources
BS2 No observations of NM_000546.6:c.-29+121G>T in unaffected females ≥60 years without cancer have been reported. Zero qualifying individuals = BS2 not met per TP53 VCEP specifications (Supporting requires at least 2-3 such individuals from a single source). Details ▾Hide ▴
Evidence considered
- Variant absent from all databases. No unaffected carrier data available.
Still missing
- No data on unaffected elderly controls carrying this variant.
BS3 No functional studies demonstrating a benign effect for NM_000546.6:c.-29+121G>T have been performed. The TP53 VCEP functional assay panel (Kato, Giacomelli, Kotler, Funk, Kawaguchi) covers missense amino acid changes and small in-frame deletions only. This deep intronic variant is outside the scope of eligible functional assays. Details ▾Hide ▴
Evidence considered
- Deep intronic variant not covered by TP53 VCEP functional assay framework. No functional data exist.
Still missing
- No minigene assay or RNA analysis demonstrating normal splicing.
BS4 No segregation data demonstrating lack of co-segregation with LFS-associated cancers have been reported for NM_000546.6:c.-29+121G>T. No family studies available. Details ▾Hide ▴
Evidence considered
- No family or segregation data identified.
Still missing
- No pedigree data showing non-segregation in affected families.
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, exon deletions) in TP53. NM_000546.6:c.-29+121G>T is a deep intronic substitution at position +121 in intron 1, which does not fall into any PVS1 null-variant bucket. SpliceAI predicts no splicing impact (max delta = 0.00). Not applicable per TP53 VCEP PVS1 flowchart. Details ▾Hide ▴
Evidence considered
- Deep intronic substitution at c.-29+121 (intron 1)
- not a canonical splice site variant
- SpliceAI max delta 0.00 predicts no cryptic splice effect.
Sources
PS1 N/APS1 applies to variants producing the same amino acid change as a previously established P/LP variant per TP53 VCEP specifications. NM_000546.6:c.-29+121G>T is an intronic variant that does not alter the amino acid sequence. No protein change to compare. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid change produced.
PM1 N/APM1 applies to missense variants at TP53 hotspot codons (175, 245, 248, 249, 273, 282) or with ≥2 somatic occurrences at cancerhotspots.org for the same amino acid change. NM_000546.6:c.-29+121G>T is an intronic substitution, not a missense variant. No amino acid residue is affected. Details ▾Hide ▴
Evidence considered
- Intronic variant
- does not alter any amino acid codon.
PM3 VCEPRecessive disorder criterion. Not applicable to TP53/Li-Fraumeni syndrome (autosomal dominant). Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPProtein length change criterion. Not applicable: this is a single nucleotide substitution, not an in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to missense variants at an amino acid residue where a different P/LP missense change has been established per TP53 VCEP specifications. NM_000546.6:c.-29+121G>T is an intronic variant that does not alter the amino acid sequence. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid residue affected per pm5_candidates assessment.
Sources
pm5_candidates
PM6 VCEPThe TP53 VCEP combines PS2 and PM6 under a unified de novo scoring system; PM6 as a standalone criterion is not applicable per the VCEP specifications. De novo assessment is addressed under PS2. Details ▾Hide ▴
Evidence considered
- PS2/PM6 combined under TP53 VCEP de novo scoring.
PP2 VCEPPP2 is not applicable per TP53 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Criterion marked not applicable by TP53 VCEP v2.4.0.
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per TP53 VCEP v2.4.0. Details ▾Hide ▴
Evidence considered
- Criterion marked not applicable by TP53 VCEP v2.4.0.
BP1 VCEPBP1 is not applicable per TP53 VCEP specifications. This rule code does not apply to TP53 as truncating variants account for only a portion of disease-causing variants. Details ▾Hide ▴
Evidence considered
- Criterion marked not applicable by TP53 VCEP v2.4.0.
BP2 VCEPBP2 is not applicable per TP53 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Criterion marked not applicable by TP53 VCEP v2.4.0.
BP3 VCEPIn-frame deletions/insertions in repetitive region without known function. Not applicable: this is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP5 VCEPBP5 is not applicable per TP53 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Criterion marked not applicable by TP53 VCEP v2.4.0.
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per TP53 VCEP v2.4.0. Details ▾Hide ▴
Evidence considered
- Criterion marked not applicable by TP53 VCEP v2.4.0.
PS5 N/ANot assessed per instruction. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.-29+121G>T
- Protein (HGVS p.)
- NP_000537.3:p.?
- GRCh38
- chr17:7687256 C>A
- GRCh37
- chr17:7590574 C>A
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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+121G>T is an intronic variant outside ±1,2 splice positions with SpliceAI max delta = 0.00. Per TP53 VCEP BP4 rules, intronic variants outside ±1,2 positions with SpliceAI ≤ 0.1 meet BP4_Supporting. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (≤ 0.1). Intronic variant outside ±1
- 2 canonical splice positions.
Sources
BP7 SupportingNM_000546.6:c.-29+121G>T is an intronic variant at position +121 (beyond +7 from the splice donor) with SpliceAI max delta = 0.00, predicting no impact on splicing. Per TP53 VCEP BP7_Supporting rule: intronic variants at or beyond +7 to -21 positions with SpliceAI ≤ 0.1 and BP4 met qualify for BP7_Supporting. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.-29+121 (>+7 from splice donor). SpliceAI max delta = 0.00 (≤ 0.1). BP4_Supporting is met.
Sources
PP3 For intronic variants outside ±1,2 splice positions, TP53 VCEP PP3_Supporting requires SpliceAI ≥ 0.2. SpliceAI max delta for NM_000546.6:c.-29+121G>T is 0.00, well below the threshold. No predicted splice-altering effect. PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0). Does not meet PP3_Supporting threshold of ≥0.2.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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%2B121G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7590574-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7687256-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7687256-C-A
- 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+121G%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.
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).