About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.214_215delinsTG, p.(Pro72Cys)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0), which is below the VCEP PM2_Supporting threshold of <0.00003 (0.003%).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
8 reported laboratory submissions
7 Uncertain significance · 1 Likely benign.
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105026609, n = 2 times).
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: 1 met · 11 not met · 4 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
NM_000546.5:c.214_215delinsTG (p.Pro72Cys) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting per TP53 VCEP criteria (allele frequency <0.003%).
PVS1 is not applicable as the variant is an in-frame delins resulting in a single amino acid substitution (p.Pro72Cys), not a null variant covered by the VCEP PVS1 flowchart.
No functional data (PS3/BS3) is available for this variant; p.Pro72Cys is not listed in the VCEP Functional-worksheet and no variant-specific functional studies were identified in the reviewed literature.
No pathogenic or likely pathogenic variant has been established at codon 72 (Pro72), which precludes application of PS1 and PM5. All single-nucleotide missense variants at this residue receive BP4_moderate per the VCEP.
In silico scores (REVEL, BayesDel) are not computable for delins variants, precluding PP3/BP4 assessment.
Codon 72 is not a recognized TP53 hotspot; the variant lies outside VCEP-designated hotspot codons 175, 245, 248, 249, 273, and 282, and is not listed in cancerhotspots.org.
No proband clinical data, de novo observations, segregation data, or elderly cancer-free carrier data are available for this variant, precluding PS2, PS4, PP1, PP4, BS2, and BS4.
This variant has been reported in ClinVar as Uncertain Significance, with 7 clinical laboratories reporting Uncertain Significance, 1 reporting Likely Benign, and the ClinGen TP53 VCEP Expert Panel classifying as Uncertain Significance (ClinVar ID: 182953).
Applying the TP53 VCEP Tavtigian point-based classification system: only PM2_Supporting (1 point) is met, yielding a total of 1 point, which falls within the Uncertain Significance range (-1 to 5 points).
No criteria match.
Met · 1
PM2 SupportingNM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0), which is below the VCEP PM2_Supporting threshold of <0.00003 (0.003%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exome)
- Absent from gnomAD v4.1 (exome)
- Absent from gnomAD-Canada v1.0
Sources
Not met · 11 · evaluated, threshold not reached
PS1 No pathogenic or likely pathogenic variant has been established at codon 72 (Pro72) per the TP53 VCEP. The VCEP PP3-BP4 spreadsheet assigns BP4_moderate to all single-nucleotide missense variants at this residue. The functional worksheet lists R72 variants with 'No evidence' or BS3 codes. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4 codes: c.214C>T (Pro72Ser) = BP4_moderate
- c.214C>G (Pro72Ala) = BP4_moderate
- c.215C>T (Pro72Leu) = BP4_moderate
- c.215C>G (Pro72Arg) = BP4_moderate
- No P/LP variant established at Pro72 per TP53 VCEP
Sources
PS2 No de novo observation has been reported for NM_000546.5:c.214_215delinsTG. No proband data with confirmed parentage is available. Details ▾Hide ▴
Evidence considered
- No de novo data identified in ClinVar or literature
Still missing
- De novo testing or parental studies would be needed to apply PS2
PS4 No probands meeting Li-Fraumeni syndrome clinical criteria with this variant have been identified in the available evidence. No PS4 points can be scored without proband-level clinical data. Details ▾Hide ▴
Evidence considered
- No proband data available
- no LFS-associated cancer diagnoses linked to this variant
Still missing
- Proband clinical data and LFS cancer phenotyping needed to calculate PS4 points per VCEP scoring table
Sources
PM1 Codon 72 (Pro72) is not among the VCEP-designated TP53 hotspot codons (175, 245, 248, 249, 273, 282). The variant is not listed in cancerhotspots.org with sufficient somatic occurrences for the same amino acid change. Details ▾Hide ▴
Evidence considered
- Pro72 is not a recognized TP53 hotspot codon per VCEP
- Variant not listed in statistically significant hotspot
- Exact variant not listed in cancerhotspots.org
Sources
PM5 The variant is a delins resulting in a single amino acid substitution (Pro72Cys) rather than a classic single-nucleotide missense variant. Regardless, no pathogenic or likely pathogenic missense variant has been established at Pro72 per the TP53 VCEP. PM5 requires a different established pathogenic variant at the same residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search did not find any same-residue comparator variants
- No pathogenic or likely pathogenic variant established at Pro72 per TP53 VCEP
Sources
cspec ↗pm5_candidates
PP1 No cosegregation data is available for this variant. No families with multiple affected members carrying NM_000546.5:c.214_215delinsTG have been reported. Details ▾Hide ▴
Evidence considered
- No cosegregation data identified
Still missing
- Family studies with segregation analysis needed to apply PP1
PP4 No patient-specific phenotype or variant allele fraction (VAF) data is available. PP4 requires observation of the variant at low VAF (5-35%) suggestive of somatic mosaicism or constitutional mosaicism. Details ▾Hide ▴
Evidence considered
- No VAF data or clinical phenotype information available
Still missing
- Patient phenotype and VAF data needed
Sources
BA1 NM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The BA1 threshold of FAF ≥ 0.001 (0.1%) in any continental subpopulation is not met. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- does not meet BA1 threshold
Sources
BS1 NM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The BS1 threshold of FAF ≥ 0.0003 (0.03%) in any continental subpopulation is not met. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- does not meet BS1 threshold
Sources
BS2 No data is available on healthy elderly females (≥60 years without cancer) carrying this variant. BS2 requires ≥2 unrelated females meeting these criteria from a single source. Details ▾Hide ▴
Evidence considered
- No data on healthy elderly female carriers identified
Still missing
- Population data on elderly cancer-free female carriers needed
BS4 No segregation data is available. BS4 requires lack of segregation in affected family members diagnosed with LFS-associated cancers. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Family segregation data needed
Not assessed · 4 · no assessment recorded
PS3 The variant p.Pro72Cys is not listed in the TP53 VCEP Functional-worksheet (Supplementary Table S3). No functional data from Kato, Funk, Giacomelli, Kotler, or Kawaguchi assays is available. None of the reviewed publications contain variant-specific functional evidence for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP Functional-worksheet (P72C not listed among 4195 entries)
- No Kotler assay data available for small deletion path in functional flowchart
Still missing
- Functional assay data (Kato
- Funk
- Giacomelli
- Kotler
- Kawaguchi) not available for Pro72Cys
- Variant-specific functional studies not identified in literature
Sources
vcep_functional_worksheet
PP3 REVEL and BayesDel scores are not computable for delins variants — they are designed for single nucleotide variants. The VCEP PP3-BP4-codes.xlsx does not include this variant. No in silico pathogenicity prediction can be applied under the VCEP framework. Details ▾Hide ▴
Evidence considered
- REVEL not available (not an SNV)
- BayesDel not available (not an SNV)
- Variant not listed in VCEP PP3-BP4-codes.xlsx
- SpliceAI not applicable (variant is exonic missense
- no splice prediction needed)
Still missing
- In silico tools not designed for delins variants
- no computational prediction available
Sources
vcep_pp3_bp4_codes
BS3 The variant p.Pro72Cys is not listed in the TP53 VCEP Functional-worksheet (Supplementary Table S3). No functional data from eligible assays (Kato, Funk, Giacomelli, Kotler, Kawaguchi) is available. The variant lacks pre-assigned functional codes from the VCEP. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP Functional-worksheet (P72C not listed)
- No Kato assay data
- no Kotler deletion assay data
Still missing
- Functional assay data needed to assess BS3
Sources
vcep_functional_worksheet
BP4 BayesDel and REVEL scores are not computable for delins variants. The VCEP PP3-BP4-codes.xlsx does not include this variant. While single-nucleotide substitutions at Pro72 consistently receive BP4_moderate (BayesDel scores from -0.10 to -0.21), these scores cannot be directly applied to a delins variant. Details ▾Hide ▴
Evidence considered
- REVEL not available (not an SNV)
- BayesDel not available (not an SNV)
- Nearby SNVs at Pro72 get BP4_moderate
- but scores not transferable
- SpliceAI not applicable
Still missing
- In silico scores not available for delins variants
Sources
vcep_pp3_bp4_codes
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000546.5:c.214_215delinsTG results in a single amino acid substitution (p.Pro72Cys), not a null variant (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion). PVS1 applies only to null variants per the TP53 VCEP PVS1 flowchart. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins producing a single amino acid substitution (Pro72Cys)
- not a null variant
- TP53 VCEP PVS1 flowchart explicitly covers nonsense
- frameshift
- canonical splice
- initiation codon
- and CNV variants only
Sources
PM4 VCEPPM4 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. The VCEP does not use PM4 for TP53 variant classification. Details ▾Hide ▴
PM6 VCEPPM6 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Details ▾Hide ▴
PP2 VCEPPP2 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Missense variants account for the majority of pathogenic TP53 variants. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable by the ClinGen SVI VCEP Review Committee. The TP53 VCEP does not use this criterion. Details ▾Hide ▴
BP1 VCEPBP1 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Truncating variants account for only a portion of disease-causing TP53 variants. Details ▾Hide ▴
BP2 VCEPBP2 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Details ▾Hide ▴
BP3 VCEPBP3 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. This criterion concerns in-frame deletions/insertions in repetitive regions without known function, which is not assessed under the VCEP. Details ▾Hide ▴
BP5 VCEPBP5 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Details ▾Hide ▴
BP6 VCEPBP6 is designated as Not Applicable by the ClinGen SVI VCEP Review Committee. The TP53 VCEP does not use this criterion. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) or intronic variants. NM_000546.5:c.214_215delinsTG is neither synonymous nor intronic — it results in a missense substitution (p.Pro72Cys). Details ▾Hide ▴
Evidence considered
- Variant is not synonymous and not intronic
- results in Pro72Cys missense change
Sources
PS5 N/APS5 is not part of the TP53 VCEP framework. The VCEP uses PP5, which is designated as Not Applicable per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.214_215delinsTG
- Protein (HGVS p.)
- NP_000537.3:p.(Pro72Cys)
- GRCh38
- chr17:7676154 GG>CA
- GRCh37
- chr17:7579472 GG>CA
- ClinVar
- 182953
- COSMIC
- COSV105026609
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
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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 REVEL and BayesDel scores are not computable for delins variants — they are designed for single nucleotide variants. The VCEP PP3-BP4-codes.xlsx does not include this variant. No in silico pathogenicity prediction can be applied under the VCEP framework. Details ▾Hide ▴
Evidence considered
- REVEL not available (not an SNV)
- BayesDel not available (not an SNV)
- Variant not listed in VCEP PP3-BP4-codes.xlsx
- SpliceAI not applicable (variant is exonic missense
- no splice prediction needed)
Still missing
- In silico tools not designed for delins variants
- no computational prediction available
Sources
vcep_pp3_bp4_codes
BP4 BayesDel and REVEL scores are not computable for delins variants. The VCEP PP3-BP4-codes.xlsx does not include this variant. While single-nucleotide substitutions at Pro72 consistently receive BP4_moderate (BayesDel scores from -0.10 to -0.21), these scores cannot be directly applied to a delins variant. Details ▾Hide ▴
Evidence considered
- REVEL not available (not an SNV)
- BayesDel not available (not an SNV)
- Nearby SNVs at Pro72 get BP4_moderate
- but scores not transferable
- SpliceAI not applicable
Still missing
- In silico scores not available for delins variants
Sources
vcep_pp3_bp4_codes
BP7 N/ABP7 applies to synonymous (silent) or intronic variants. NM_000546.5:c.214_215delinsTG is neither synonymous nor intronic — it results in a missense substitution (p.Pro72Cys). Details ▾Hide ▴
Evidence considered
- Variant is not synonymous and not intronic
- results in Pro72Cys missense change
Sources
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 16818505 ↗Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y).Ferrone M et al. · 2006Reports functional analysis of p53(C238Y) in malignant peripheral nerve sheath tumors, demonstrating preserved wild-type activity via molecular modeling and transcription assays. NM_000546.5:c.214_215delinsTG was not identified in this paper.Does not name this variant
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PMID 17606709 ↗Transcriptional functionality of germ line p53 mutants influences cancer phenotype.Monti P et al. · 2007Characterizes transcriptional functionality of germline p53 mutants and their influence on cancer phenotype severity in Li-Fraumeni syndrome. NM_000546.5:c.214_215delinsTG was not identified in this paper.Does not name this variant
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PMID 20407015 ↗Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.Jordan JJ et al. · 2010Examines altered-function p53 missense mutations in breast cancers and their effects on transactivation from promoter response elements. NM_000546.5:c.214_215delinsTG was not identified in this paper.Does not name this variant
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PMID 21343334 ↗Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.Monti P et al. · 2011Assesses dominant-negative features of germline TP53 mutants and their limited impact on cancer outcomes in Li-Fraumeni syndrome families. NM_000546.5:c.214_215delinsTG was not identified in this paper.Does not name this variant
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PMID 21519010 ↗TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.Jädersten M et al. · 2011Reports TP53 mutations in low-risk myelodysplastic syndromes with del(5q) as predictors of disease progression. NM_000546.5:c.214_215delinsTG was not identified in this paper.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.The ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a methods guideline, not a variant-specific study. NM_000546.5:c.214_215delinsTG was not mentioned.Does not name this variant
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PMID 26230955 ↗TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.Reports TP53 mutations in de novo acute myeloid leukemia with longitudinal follow-up. A different variant at codon 72 (c.215_225del, P72RfsX73) was identified, but NM_000546.5:c.214_215delinsTG was not found in this paper.Does not name this variant
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PMID 27276561 ↗Genomic Classification and Prognosis in Acute Myeloid Leukemia.Presents genomic classification and prognosis in acute myeloid leukemia across 1540 patients. NM_000546.5:c.214_215delinsTG was not identified in this paper.Does not name this variant
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
7 Uncertain significance · 1 Likely benign
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/182953/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579472-GG-CA?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7676154-GG-CA?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7676154-GG-CA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.214_…
- OncoKB ↗www.oncokb.org/gene/TP53/P72C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122051069
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 182953)
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; COSV105026609, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.