About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.919+4A>G, 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
NM_000546.6:c.919+4A>G is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP BP4 rule, intronic variants outside ±1,2 with SpliceAI ≤0.1 qualify for BP4_Supporting. The SpliceAI max delta score is 0.00, meeting this threshold.
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) = 0 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
0.000 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.
26 criteria with recorded statuses: 2 met · 4 not met · 7 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
NM_000546.6:c.919+4A>G is an intronic variant at the +4 position of intron 8 in TP53, evaluated under the ClinGen TP53 VCEP Specifications v2.4.0. The variant is absent from gnomAD v2.1 and v4.1, supporting PM2_Supporting.
SpliceAI predicts no splicing impact (max delta score 0.00). As an intronic variant outside the ±1,2 canonical splice positions with SpliceAI ≤0.1, BP4_Supporting is met.
PVS1 is not applicable as the variant lies outside the canonical ±1,2 splice donor/acceptor positions addressed by the VCEP PVS1 flowchart. PS3/BS3 functional codes are not applicable as they address missense variants and small in-frame deletions only. The variant is not located in a VCEP-specified mutational hotspot and has no amino acid change, so PM1 and PM5 are not applicable.
With one pathogenic supporting code (PM2_Supporting, +1 point) and one benign supporting code (BP4_Supporting, -1 point), the total point value is 0. Under the Tavtigian point-based system adopted by the TP53 VCEP v2.4.0, a score of 0 falls in the range of Uncertain Significance (-1 to 5 points).
No criteria match.
Met · 2
PM2 SupportingNM_000546.6:c.919+4A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%). Details ▾Hide ▴
BP4 SupportingNM_000546.6:c.919+4A>G is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP BP4 rule, intronic variants outside ±1,2 with SpliceAI ≤0.1 qualify for BP4_Supporting. The SpliceAI max delta score is 0.00, meeting this threshold. Details ▾Hide ▴
Evidence considered
- Intronic variant at +4 position (outside ±1
- 2)
- SpliceAI max delta 0.00 ≤0.1
Sources
Not met · 4 · evaluated, threshold not reached
PP3 For intronic splice variants outside the ±1,2 canonical positions, the TP53 VCEP PP3 rule requires SpliceAI ≥0.2. NM_000546.6:c.919+4A>G has a SpliceAI max delta score of 0.00, which does not meet this threshold. There is no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- does not meet PP3 threshold of ≥0.2 for intronic variants
Sources
BA1 The TP53 VCEP BA1 rule requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in gnomAD continental subpopulations (excluding founder-influenced groups). NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 and v4.1, far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- does not meet BA1 threshold of FAF ≥0.001
Sources
BS1 The TP53 VCEP BS1 rule requires a filtering allele frequency (FAF) ≥0.0003 (0.03%) but <0.001 in gnomAD continental subpopulations. NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 and v4.1, far below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- does not meet BS1 threshold of FAF ≥0.0003
Sources
BP7 The TP53 VCEP BP7_Supporting rule requires an intronic variant at or beyond +7 to -21 positions with SpliceAI ≤0.1 and BP4 met. NM_000546.6:c.919+4A>G is at the +4 position, which does not satisfy the 'at or beyond +7' requirement. BP7_Strong requires RNA splicing assay data demonstrating no splicing aberration, which is not available. BP7 criteria are not met. Details ▾Hide ▴
Evidence considered
- Intronic variant at +4 position (not at or beyond +7)
- SpliceAI 0.00 but position does not qualify for BP7_Supporting
- No RNA splicing assay data for BP7_Strong
Still missing
- No RNA splicing assay data available
Sources
Not assessed · 7 · no assessment recorded
PS1 No other nucleotide substitutions at the c.919+4 position have been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. The VCEP PS1 rule requires a different nucleotide change at the same position previously determined to be pathogenic following VCEP specifications. Details ▾Hide ▴
Evidence considered
- No VCEP-classified pathogenic/likely pathogenic variants identified at the c.919+4 position
Still missing
- No comparator variants at the same nucleotide position with VCEP classification
Sources
PS2 No de novo observations for NM_000546.6:c.919+4A>G were identified in the available literature. The VCEP PS2 rule requires proband points tallied using the LFS cancer scoring table, which requires proband-level clinical data. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in literature search
Still missing
- No proband-level de novo data available
PS4 No proband data with Li-Fraumeni syndrome-associated cancers were available for NM_000546.6:c.919+4A>G. The VCEP PS4 rule requires tallying proband cancer points (strongly associated cancers: 4 points; moderately associated: 2 points) against strength thresholds (Supporting: 1-1.5, Moderate: 2-3.5, Strong: 4-7.5, Very Strong: ≥8). Details ▾Hide ▴
Evidence considered
- No proband-level cancer phenotype data available for this variant
Still missing
- No proband data with LFS cancer phenotypes identified
Sources
PP1 No cosegregation data were available for NM_000546.6:c.919+4A>G. The VCEP PP1 rule requires cosegregation observed in ≥3 meioses (Supporting), 5-6 meioses (Moderate), or ≥7 meioses (Strong) across one or more families. Details ▾Hide ▴
Evidence considered
- No cosegregation data identified in available literature
Still missing
- No family segregation data available
Sources
PP4 No observations of NM_000546.6:c.919+4A>G with variant allele fraction (VAF) data were available. The VCEP PP4 rule requires one or more observations with VAF 5-35% (Supporting) or ≥2 independent observations with VAF 5-25% (Moderate). Details ▾Hide ▴
Evidence considered
- No VAF observation data available for this variant
Still missing
- No somatic/low-VAF observation data available
Sources
BS2 No data were available on unrelated females ≥60 years of age without cancer carrying NM_000546.6:c.919+4A>G. The VCEP BS2 rule requires ≥2 such individuals from a single source (Supporting), 4-7 (Moderate), or ≥8 (Strong). Details ▾Hide ▴
Evidence considered
- No data on healthy older females carrying this variant
Still missing
- No population data on cancer-free females ≥60 years
Sources
BS4 No segregation data were available to assess lack of segregation in affected family members. The VCEP BS4 rule requires lack of segregation in family members diagnosed with LFS-associated cancers. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No segregation data in LFS-affected families
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000546.6:c.919+4A>G is an intronic variant at the +4 position, which is outside the canonical ±1,2 splice consensus. The TP53 VCEP PVS1 flowchart applies to canonical splice sites (±1,2 positions) only. SpliceAI predicts no splicing impact (max delta 0.00). PVS1 is not applicable to non-canonical intronic variants under the VCEP framework. Details ▾Hide ▴
Evidence considered
- Intronic variant at +4 position
- outside canonical ±1
- 2 splice donor/acceptor sites
- SpliceAI max delta score 0.00 predicts no aberrant splicing
Sources
PS3 N/AThe TP53 VCEP functional assay criteria (PS3/BS3) apply to missense variants and small in-frame deletions evaluated through protein function assays (Kato, Funk, Giacomelli, Kotler, Kawaguchi). NM_000546.6:c.919+4A>G is an intronic variant that does not alter an amino acid and is not covered by the VCEP functional assay framework. Details ▾Hide ▴
Evidence considered
- Intronic variant with no amino acid change
- not eligible for VCEP functional assay assessment
Sources
cspec ↗vcep_functional_worksheet
PM1 N/AThe TP53 VCEP PM1 rule applies to missense variants within specified hotspot codons (175, 245, 248, 249, 273, 282) or missense variants with ≥10 somatic occurrences at the same amino acid change in cancerhotspots.org. NM_000546.6:c.919+4A>G is an intronic variant with no amino acid change. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense change at a VCEP-specified hotspot codon
Sources
PM5 N/AThe TP53 VCEP PM5 rule applies to missense variants at an amino acid residue where other missense variants have been determined to be pathogenic/likely pathogenic. NM_000546.6:c.919+4A>G is an intronic variant with no amino acid change, and the PM5 candidate search confirmed no eligible comparator variants. Details ▾Hide ▴
Evidence considered
- Intronic variant with no amino acid residue
- PM5 candidate search found no eligible comparators
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework. Details ▾Hide ▴
PP2 VCEPPP2 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework. Details ▾Hide ▴
PP5 VCEPPP5 is designated Not Applicable for This VCEP in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 N/AThe TP53 VCEP functional assay criteria (PS3/BS3) apply to missense variants and small in-frame deletions evaluated through protein function assays. NM_000546.6:c.919+4A>G is an intronic variant with no amino acid change and is not covered by the VCEP functional assay framework. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not eligible for VCEP functional assay assessment
Sources
cspec ↗vcep_functional_worksheet
BP1 VCEPBP1 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. The VCEP states this rule code does not apply to TP53, as truncating variants account for only a portion of disease-causing variants. Details ▾Hide ▴
BP2 VCEPBP2 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework. Details ▾Hide ▴
BP5 VCEPBP5 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework. Details ▾Hide ▴
BP6 VCEPBP6 is designated Not Applicable for This VCEP in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/APS5 is not defined in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework. Details ▾Hide ▴
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.919+4A>G
- Protein (HGVS p.)
- NP_000537.3:p.?
- GRCh38
- chr17:7673697 T>C
- GRCh37
- chr17:7577015 T>C
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
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 SupportingNM_000546.6:c.919+4A>G is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP BP4 rule, intronic variants outside ±1,2 with SpliceAI ≤0.1 qualify for BP4_Supporting. The SpliceAI max delta score is 0.00, meeting this threshold. Details ▾Hide ▴
Evidence considered
- Intronic variant at +4 position (outside ±1
- 2)
- SpliceAI max delta 0.00 ≤0.1
Sources
PP3 For intronic splice variants outside the ±1,2 canonical positions, the TP53 VCEP PP3 rule requires SpliceAI ≥0.2. NM_000546.6:c.919+4A>G has a SpliceAI max delta score of 0.00, which does not meet this threshold. There is no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- does not meet PP3 threshold of ≥0.2 for intronic variants
Sources
BP7 The TP53 VCEP BP7_Supporting rule requires an intronic variant at or beyond +7 to -21 positions with SpliceAI ≤0.1 and BP4 met. NM_000546.6:c.919+4A>G is at the +4 position, which does not satisfy the 'at or beyond +7' requirement. BP7_Strong requires RNA splicing assay data demonstrating no splicing aberration, which is not available. BP7 criteria are not met. Details ▾Hide ▴
Evidence considered
- Intronic variant at +4 position (not at or beyond +7)
- SpliceAI 0.00 but position does not qualify for BP7_Supporting
- No RNA splicing assay data for BP7_Strong
Still missing
- No RNA splicing assay data available
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.919%2B4A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577015-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7673697-T-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.919%…
- OncoKB ↗www.oncokb.org/gene/TP53/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.919+4A%3EG
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 = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).