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TP53c.997_1006delLikely pathogenic
Print report
Variant interpretation report

TP53 c.997_1006del, p.(Arg333SerfsTer9)

NM_000546.6:c.997_1006del NP_000537.3:p.(Arg333SerfsTer9) Frameshift · exon 10 View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stress such as DNA damage by switching on genes that trigger cell cycle arrest, DNA repair, senescence, or programmed cell death. In healthy cells, p53 is kept at low levels by constant degradation, but stress signals stabilize and activate it to protect against damaged cells surviving and dividing. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a condition marked by a high risk of developing multiple cancers at a young age. TP53 is the most commonly mutated gene across human cancers, and loss of its normal function promotes tumor growth, spread, drug resistance, and genomic instability.

NCBI Gene ↗ OncoKB ↗
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. 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met, very strong: the exon 10 frameshift creates a PTC at p.341, upstream of p.Lys351 and outside the exon 10 NMD-escape region.

PM2Supporting
PM2 · supporting

Met at supporting strength: the variant is absent from gnomAD v4.1 and v2.1, with observed frequency 0, below the TP53 PM2 threshold of <0.00003.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PVS1 very strong (+8) plus PM2 supporting (+1) total 9 points under the ClinGen TP53 Expert Panel Version 2.4 framework.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

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
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 2 not met · 6 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The TP53 VCEP-specific PVS1 flowchart governs this exonic frameshift and supports undowngraded PVS1 at very strong strength because the predicted PTC is upstream of p.Lys351 and is expected to undergo NMD.

PM4 and BP3 are not applicable under the TP53 VCEP specification and do not fit this frameshift consequence.

The queried variant is a frameshift, while the governing TP53 functional flowchart and worksheet specify functional PS3/BS3 assignments for missense variants and small in-frame deletions.

No exact variant notation was found in either governing functional file, and the available R333 assay rows concern different missense substitutions.

Accordingly, neither PS3 nor BS3 is applicable from the consulted functional evidence; no functional code was inferred from another criterion or from unrelated truncating-variant literature.

Population evidence supports PM2 at supporting strength because the variant is absent from the applicable all-comers gnomAD v4.1 and v2.1 datasets.

BA1 and BS1 are not met because no population allele frequency is reported, and BS2 cannot be assessed without qualifying healthy carrier-level observations.

Met · 2

PVS1 Very strongMet, very strong: the exon 10 frameshift creates a PTC at p.341, upstream of p.Lys351 and outside the exon 10 NMD-escape region. Details ▾Hide ▴
Reasoning

NM_000546.6:c.997_1006del is a TP53 frameshift in exon 10 producing NP_000537.3:p.(Arg333SerfsTer9), with the predicted premature termination codon at p.341, upstream of p.Lys351. The TP53 VCEP PVS1 flowchart assigns full PVS1 to frameshift-induced PTCs upstream of p.Lys351 when the PTC is not in exon 11 or the 3'-most 50 nucleotides of exon 10, because NMD is predicted. The variant is in the biologically relevant NM_000546.6 transcript and is not a canonical splice-site variant; therefore no splicing-worksheet assignment or downgrade applies. The literal strength is recorded as "very strong" for an undowngraded PVS1 call.

Rule
TP53 VCEP v2.4 PVS1 flowchart: frameshift-induced PTC upstream of p.Lys351 and outside exon 11 or the 3'-most 50 nucleotides of exon 10 receives full PVS1.
Evidence considered
  • The normalized consequence is NM_000546.6:c.997_1006del, a frameshift producing NP_000537.3:p.(Arg333SerfsTer9), with predicted protein position_last_predicted 341 and original terminal residue 394.
  • Variant Validator places the deletion entirely in exon 10 of the biologically relevant NM_000546.6 transcript.
  • The TP53 VCEP PVS1 flowchart assigns PVS1 to a frameshift-induced PTC upstream of p.Lys351 when the PTC is not in exon 11 or the 3'-most 50 nucleotides of exon 10; this variant meets that branch.
  • The case data report no SpliceAI score, but SpliceAI is not needed for this exonic frameshift PVS1 branch and the variant is not a canonical splice-site alteration.
Still missing
  • No direct variant entry was found in PVS1-Flowchart.pdf.txt; its generic TP53 frameshift branch is applicable.
  • No direct variant entry was found in PVS1-Splicing-Worksheet.xlsx.txt; that worksheet is limited to canonical splice-site variants and is not applicable here.
Sources
cspec ↗vcep_pvs1_flowchart
PM2 SupportingMet at supporting strength: the variant is absent from gnomAD v4.1 and v2.1, with observed frequency 0, below the TP53 PM2 threshold of <0.00003. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies PM2 at supporting strength when the allele frequency is below 0.00003 in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group's frequency must remain below 0.00004. NM_000546.6:c.997_1006del is absent from gnomAD v4.1 and gnomAD v2.1, giving an observed allele count of zero and an allele frequency of 0, below both thresholds. No founder-effect ancestry exception is implicated because no variant alleles are reported.

Rule
TP53 VCEP PM2 supporting: allele frequency <0.00003 in gnomAD; if multiple alleles are present within an ancestry group, that group's frequency must be <0.00004.
Evidence considered
  • The TP53 VCEP Version 2.4 PM2 rule is supporting only and requires allele frequency <0.00003 in gnomAD; if multiple alleles are present in an ancestry group, that group must have frequency <0.00004.
  • The queried frameshift variant NM_000546.6:c.997_1006del is reported absent from gnomAD v4.1 and gnomAD v2.1, corresponding to observed allele count 0 and allele frequency 0 in the reported datasets.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Not met · 2 · evaluated, threshold not reached

BA1 Not met: the variant is absent from gnomAD v4.1 and v2.1, rather than reaching the TP53 BA1 threshold of FAF >=0.001. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies BA1 at stand-alone strength when the filtering allele frequency is at least 0.001 in a qualifying continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles. NM_000546.6:c.997_1006del is absent from gnomAD v4.1 and gnomAD v2.1; therefore no qualifying allele frequency reaches the BA1 threshold.

Rule
TP53 VCEP BA1 stand-alone: FAF >=0.001 in one qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
Evidence considered
  • The TP53 VCEP Version 2.4 rule requires filtering allele frequency (FAF) >=0.001 in a qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
  • The queried frameshift variant NM_000546.6:c.997_1006del is reported absent from gnomAD v4.1 and gnomAD v2.1, so no BA1-level population frequency is present.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS1 Not met: the variant is absent from gnomAD v4.1 and v2.1, rather than having TP53 BS1 FAF >=0.0003 and <0.001. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies BS1 at strong strength when the filtering allele frequency is at least 0.0003 but below 0.001 in a qualifying continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles. NM_000546.6:c.997_1006del is absent from gnomAD v4.1 and gnomAD v2.1, so the BS1 frequency interval is not met.

Rule
TP53 VCEP BS1 strong: FAF >=0.0003 and <0.001 in one qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
Evidence considered
  • The TP53 VCEP Version 2.4 rule requires FAF >=0.0003 and <0.001 in one qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
  • The queried frameshift variant NM_000546.6:c.997_1006del is reported absent from gnomAD v4.1 and gnomAD v2.1, so no BS1-level population frequency is present.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Not assessed · 6 · no assessment recorded

PS2 Not assessed: no proband cancer, parental testing, or confirmed parentage data are available to calculate the TP53 VCEP PS2 point total. Details ▾Hide ▴
Reasoning

The TP53 VCEP version 2.4 specifies that de novo evidence is assessed exclusively with PS2, replacing PM6, and requires de novo points based on confirmed maternity and paternity plus the proband's LFS-associated cancer type. The governing LFS cancer table assigns 4 points for a strongly associated cancer with confirmed maternity and paternity, 2 points when parentage is assumed, 2 points for a moderately associated cancer with confirmed parentage, and 1 point when parentage is assumed; PS2 strength is Supporting at 1 point, Moderate at 2-3 points, Strong at 4-7 points, and Very Strong at 8 or more points. No proband cancer, parental testing or parentage confirmation data are available for this variant, so PS2 cannot be assigned. Searches of Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt found no entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9; that table provides the governing point rules rather than a variant-specific record.

Rule
TP53 VCEP PS2: de novo points are tallied using confirmed maternity and paternity and the proband's LFS-associated cancer; 1 point = Supporting, 2-3 = Moderate, 4-7 = Strong, and >=8 = Very Strong.
Evidence considered
  • The TP53 VCEP version 2.4 states that PM6 is dropped and PS2 is used exclusively for de novo evidence.
  • The TP53 VCEP PS2 rule requires tallying de novo points by parentage confirmation and proband cancer type.
  • The governing LFS cancer table defines PS2 strength thresholds of Supporting at 1 point, Moderate at 2-3 points, Strong at 4-7 points, and Very Strong at 8 or more points.
  • No variant-specific entry was found when searching the governing LFS cancer table for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9.
Still missing
  • No proband cancer diagnosis and age are documented for PS2 point assignment.
  • No parental testing or confirmed maternity and paternity are documented.
  • No entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 Not assessed: no proband phenotype or PS4 point total is available to compare with the VCEP thresholds of 1-1.5, 2-3.5, 4-7.5, or >=8 points. Details ▾Hide ▴
Reasoning

The TP53 VCEP PS4 specification assigns points from proband clinical phenotype: Revised Chompret criteria = 0.5 point, Classic LFS criteria = 1 point, HER2-positive breast cancer diagnosed below age 40 = 0.5 point, with PS4 Supporting at 1-1.5 points, Moderate at 2-3.5, Strong at 4-7.5, and Very Strong at >=8 points. The case evidence supplied no proband cancer history, age, HER2 status, or accumulated PS4 point total, so PS4 cannot be assessed. The governing PS4-Points-Table.pdf was searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no exact-variant entry was found.

Rule
TP53 VCEP PS4: Revised Chompret = 0.5 point; Classic LFS = 1 point; HER2-positive breast cancer below age 40 = 0.5 point; Supporting = 1-1.5 points; Moderate = 2-3.5 points; Strong = 4-7.5 points; Very Strong >=8 points.
Evidence considered
  • The TP53 VCEP specification states that PS4 uses proband points: Revised Chompret 0.5, Classic LFS 1, and HER2-positive breast cancer below age 40 0.5.
  • The TP53 VCEP PS4 table defines Supporting as 1-1.5 points, Moderate as 2-3.5 points, Strong as 4-7.5 points, and Very Strong as >=8 points.
  • The supplied case evidence contains no proband phenotype or PS4 point total.
  • PS4-Points-Table.pdf was searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9, with no exact-variant entry found.
Still missing
  • No proband cancer diagnoses, ages at diagnosis, HER2 status, or Revised Chompret/Classic LFS assessment were provided.
  • No accumulated PS4 point total can be calculated.
  • No exact-variant entry was found after searching PS4-Points-Table.pdf for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9.
Sources
cspec ↗vcep_ps4_points_table
PP1 Not assessed: no affected variant-positive relatives, obligate carriers, family structure, or documented meioses are available for PP1 assignment. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires PP1 meioses to involve individuals who both carry the variant and have a relevant LFS-associated cancer, with unaffected obligate carriers allowed; 3-4 meioses support PP1, 5-6 support PP1_Moderate, and at least 7 meioses across more than one family support PP1_Strong. No affected relatives, variant-positive relatives, obligate carriers, family structure, or meiosis count are documented for this variant, so PP1 cannot be assigned. Searches of Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt found no entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9; that table provides the governing cancer definitions and thresholds rather than a variant-specific record.

Rule
TP53 VCEP PP1: 3-4 cosegregating meioses = Supporting, 5-6 = Moderate, and >=7 across more than one family = Strong; count relevant LFS cancers and unaffected obligate carriers as specified.
Evidence considered
  • The TP53 VCEP defines PP1 meioses using variant-positive individuals with relevant LFS-associated cancers and permits counting through unaffected obligate carriers.
  • The TP53 VCEP assigns PP1 Supporting for 3-4 cosegregating meioses, Moderate for 5-6, and Strong for at least 7 across more than one family.
  • No family segregation or meiosis data are documented for this variant.
  • No variant-specific entry was found when searching the governing LFS cancer table for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9.
Still missing
  • No affected relatives with relevant LFS-associated cancers and variant status are documented.
  • No unaffected obligate carriers or family structure sufficient to count meioses are documented.
  • No meiosis count is available for comparison with the TP53 VCEP thresholds of 3-4, 5-6, or at least 7 meioses.
  • No entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 Not assessed: VAF and multigene-panel context are unavailable for comparison with the VCEP PP4 ranges of 5-25% or 5-35%. Details ▾Hide ▴
Reasoning

The TP53 VCEP PP4 specification applies to a TP53 variant detected on multigene panel testing at low VAF: at least 2 independent observations with VAF 5-25% support Moderate, while observation with VAF 5-35% supports Supporting. The case evidence provides no VAF, multigene-panel context, or confirmation that the variant is constitutional mosaicism rather than clonal hematopoiesis, so PP4 cannot be assessed.

Rule
TP53 VCEP PP4: at least 2 independent observations with VAF 5-25% = Moderate; observation with VAF 5-35% = Supporting; variant must be detected on multigene panel and the rule is not used in blood cancer or when BA1/BS1 applies.
Evidence considered
  • The TP53 VCEP PP4 rule requires multigene-panel detection and assumes a somatic-origin context for low-VAF TP53 variants.
  • The VCEP assigns PP4 Moderate for at least 2 independent observations with VAF 5-25% and Supporting for observation with VAF 5-35%.
  • The case evidence does not report VAF, number of observations, multigene-panel testing, or constitutional mosaicism confirmation.
Still missing
  • No variant allele fraction was provided.
  • No multigene-panel testing context was provided.
  • No evidence distinguishes constitutional mosaicism from clonal hematopoiesis or another low-VAF source.
Sources
cspec ↗
BS2 Not assessed: no qualifying healthy female carrier count, age, cancer status, single-source provenance, or VAF data is available for the TP53 BS2 thresholds. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires 2-3 unrelated females aged at least 60 years without cancer for BS2 supporting, 4-7 for moderate, or at least 8 for strong, all from a single source; individuals with a sarcoma diagnosis at age 61 or older and variants with VAF <=35% are excluded. The available case evidence contains only population-database absence and no qualifying healthy carrier counts, ages, sex, cancer status, source coherence, or VAF data.

Rule
TP53 VCEP BS2: 2-3 qualifying unrelated females aged >=60 years without cancer from one source for supporting; 4-7 for moderate; >=8 for strong.
Evidence considered
  • The TP53 VCEP BS2 rule requires unrelated female carriers aged at least 60 years without cancer from one source: 2-3 for supporting, 4-7 for moderate, and at least 8 for strong; sarcoma diagnosed at age 61 or older is excluded.
  • No qualifying healthy-carrier observations or carrier-level demographic and clinical data are provided for this variant.
Still missing
  • A single-source dataset of unrelated female TP53 carriers is needed, including age, cancer status, sarcoma history, and any available VAF values.
Sources
cspec ↗
BS4 Not assessed: no affected relatives with relevant LFS-associated cancers and documented absence of the variant are available to establish non-segregation. Details ▾Hide ▴
Reasoning

The TP53 VCEP defines BS4 as strong evidence for lack of segregation in affected family members diagnosed with LFS-associated cancers, while cautioning that phenocopies and more than one pathogenic variant can confound apparent non-segregation. No affected family members, their cancer diagnoses, genotypes, or non-segregation observations are documented for this variant, so BS4 cannot be assigned. Searches of Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt found no entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9; that table defines the relevant cancer set rather than providing a variant-specific record.

Rule
TP53 VCEP BS4: strong evidence requires lack of segregation in affected family members diagnosed with LFS-associated cancers, with phenocopies and additional pathogenic variants considered.
Evidence considered
  • The TP53 VCEP defines BS4 as lack of segregation in affected family members diagnosed with LFS-associated cancers.
  • The TP53 VCEP cautions that phenocopies and additional pathogenic variants can confound apparent lack of segregation.
  • No affected-relative genotypes or non-segregation observations are documented for this variant.
  • No variant-specific entry was found when searching the governing LFS cancer table for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9.
Still missing
  • No affected family members with relevant LFS-associated cancers are documented.
  • No genotype results demonstrating absence of the variant in affected relatives are documented.
  • No assessment of phenocopies or additional pathogenic variants is available.
  • No entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.997_1006del produces p.(Arg333SerfsTer9), a frameshift rather than a same-amino-acid missense substitution. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies PS1 for a variant asserted as pathogenic or likely pathogenic under its framework, but the queried variant is a frameshift, NM_000546.6:c.997_1006del, p.(Arg333SerfsTer9), rather than a same-amino-acid missense substitution. Therefore the codon/residue PS1 criterion is not applicable to this variant.

Rule
PS1 is not applicable to this frameshift variant under the TP53 VCEP framework.
Evidence considered
  • The TP53 VCEP PS1 rule is framed for variants asserted as pathogenic or likely pathogenic under the TP53 specifications; this queried variant is a frameshift, not a missense substitution.
Sources
cspec ↗
PS3 N/ANot applicable: the TP53 VCEP functional worksheet covers missense or in-frame deletions, whereas this variant is a frameshift producing p.Arg333SerfsTer9. Details ▾Hide ▴
Reasoning

The TP53 VCEP functional framework explicitly covers missense variants and small in-frame deletions, and its PS3 rule for small deletions requires loss of function by the majority of available eligible assays. This variant is a frameshift, NM_000546.6:c.997_1006del, producing p.(Arg333SerfsTer9), not a missense or in-frame deletion. The authoritative Functional-worksheet.xlsx contains no exact entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9; the only R333 entries are missense substitutions and do not characterize this frameshift. Therefore PS3 is not applicable rather than inferred from unrelated missense or general truncating-variant observations.

Rule
TP53 VCEP PS3: non-functional on Kato data plus loss of function by the majority of other eligible assays; PS3_Supporting may also apply to small deletions with loss of function by the majority of available assays.
Evidence considered
  • The TP53 VCEP index declares the functional flowchart and Functional-worksheet.xlsx as governing PS3 and BS3 sources for missense variants and in-frame deletions.
  • The VCEP PS3 rule permits PS3_Supporting for small deletions with loss of function by the majority of available assays; it does not provide an applicable functional assignment for this frameshift.
  • The exact notations c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9 were searched in both governing functional files with no match; the worksheet's R333 rows are R333C, R333G, R333H, R333L, R333P, and R333S missense substitutions.
  • PMID:16007150 evaluates TP53 tetramerization-domain missense substitutions, including R333 substitutions, but does not mention or assay the queried frameshift.
Still missing
  • No exact entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Flowchart-for-application-of-functional-rule-codes.pdf.txt.
  • No exact entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Functional-worksheet.xlsx.txt; R333 entries there are missense substitutions only.
  • No variant-specific functional assay for this frameshift was identified in the consulted paper extracts.
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:16007150 ↗
PM1 N/ANot applicable: the TP53 PM1 rule covers missense hotspots, whereas c.997_1006del is a p.Arg333SerfsTer9 frameshift. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP applies PM1 to missense variants at codons 175, 245, 248, 249, 273, and 282, or to germline missense variants at the same amino-acid change with at least 10 cancerhotspots.org somatic occurrences. The queried variant is a frameshift at p.Arg333 and is not a missense variant; the vcep_materials.json domain_tables object is empty, so there is no additional authoritative domain-table entry to evaluate. PM1 is therefore not applicable.

Rule
PM1 applies only to qualifying TP53 missense hotspot variants under the governing VCEP specification; it does not apply to this frameshift.
Evidence considered
  • The TP53 VCEP PM1 rule limits application to missense variants in codons 175, 245, 248, 249, 273, and 282 or qualifying germline missense hotspot substitutions.
  • The vcep_materials.json domain_tables key is empty, so no gene-specific approved domain entry exists to extend PM1 beyond the stated missense hotspot rule.
Sources
cspec ↗vcep_hotspots_vision_instruction
PM3 VCEPNot applicable: TP53 VCEP version 2.4 explicitly designates PM3 as not applicable for this autosomal dominant disorder. Details ▾Hide ▴
Reasoning

The ClinGen TP53 Expert Panel Specifications, version 2.4, explicitly designate PM3 as not applicable. TP53-associated Li-Fraumeni syndrome is managed in this framework as an autosomal dominant disorder, so evidence for affected individuals carrying pathogenic variants in trans is not an applicable PM3 mechanism. No PM3 evidence is therefore assessed for NM_000546.6:c.997_1006del.

VCEP rule
Not Applicable
Evidence considered
  • The TP53 Expert Panel ACMG/AMP Specifications, version 2.4, list PM3 as not applicable.
  • The governing framework identifies Li-Fraumeni syndrome as autosomal dominant, making a recessive in-trans pathogenic-variant criterion inapplicable.
Sources
cspec ↗
PM4 VCEPNot applicable: PM4 is explicitly unavailable in the TP53 VCEP specification, and this variant is a frameshift rather than an in-frame change. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the TP53 VCEP v2.4 specification. The specification explicitly marks PM4 as not applicable, and the variant is a frameshift rather than an in-frame deletion or insertion for which generic PM4 might otherwise be considered.

VCEP rule
TP53 VCEP v2.4: PM4 is not applicable.
Evidence considered
  • The TP53 VCEP v2.4 specification explicitly lists PM4 as not applicable.
  • The variant consequence is frameshift, not an in-frame deletion or insertion.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 requires a missense variant, but c.997_1006del causes the frameshift p.(Arg333SerfsTer9). Details ▾Hide ▴
Reasoning

The TP53 VCEP PM5 rule requires a missense variant at an amino-acid residue where previously determined pathogenic or likely pathogenic missense variants have been observed. The queried variant is a frameshift, p.(Arg333SerfsTer9), so no missense same-residue PM5 comparison can be applied. PMID:16007150 describes TP53 R333 missense substitutions in a tetramerization-domain assay, but it does not establish a PM5-eligible pathogenic or likely pathogenic comparator and cannot change the variant-type limitation.

Rule
PM5 is not applicable because the queried variant is not missense.
Evidence considered
  • The TP53 VCEP PM5 rule requires a missense variant and qualifying pathogenic or likely pathogenic missense variants at the same amino-acid residue.
  • The queried variant is a frameshift, so same-residue missense comparators cannot establish PM5; PMID:16007150 reports R333 missense assay findings but does not characterize the queried frameshift or provide a qualifying PM5 comparator.
Sources
cspec ↗PMID:16007150 ↗
PM6 VCEPNot applicable: the TP53 VCEP explicitly replaces PM6 with PS2 for all de novo evidence. Details ▾Hide ▴
Reasoning

The TP53 VCEP version 2.4 explicitly states that PM6 is not applicable and that the VCEP has dropped PM6 in favor of PS2 exclusively for de novo evidence.

VCEP rule
TP53 VCEP PM6: Not applicable; use PS2 exclusively for de novo evidence.
Evidence considered
  • The TP53 VCEP version 2.4 states that PM6 is not applicable and uses PS2 exclusively for de novo evidence.
Sources
cspec ↗
PP2 VCEPNot applicable: the TP53 VCEP excludes PP2, and c.997_1006del is a frameshift rather than a missense variant. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP marks PP2 as not applicable. In addition, the queried variant is a frameshift rather than a missense variant, so a gene-level missense mechanism rule cannot be applied.

VCEP rule
PP2 is not applicable under the TP53 VCEP specification.
Evidence considered
  • The TP53 VCEP explicitly designates PP2 as not applicable; the queried variant is also not a missense variant.
Sources
cspec ↗
PP3 N/ANot applicable: this variant is a frameshift, outside TP53 VCEP PP3 scope for missense, splice-region/intronic, and single-amino-acid in-frame deletion variants. Details ▾Hide ▴
Reasoning

Not applicable. NM_000546.6:c.997_1006del produces the frameshift p.(Arg333SerfsTer9), p.(R333Sfs*9), and is therefore outside the TP53 VCEP PP3 scope for missense variants, splice-region/intronic variants, and specified single-amino-acid in-frame deletions. The TP53 VCEP in-silico materials were searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no entry was found in the PP3-BP4 lookup table, the PP3/BP4/BP7 flowchart text, or the single-amino-acid deletion BayesDel table. Because the variant is a truncating frameshift, SpliceAI, REVEL, and BayesDel were not evaluated for PP3.

Evidence considered
  • The case normalization identifies NM_000546.6:c.997_1006del as a frameshift producing p.(Arg333SerfsTer9) / p.(R333Sfs*9).
  • The TP53 VCEP PP3 rule specifies missense, single-amino-acid in-frame deletion, exonic splice-effect, or intronic splice-variant contexts; a frameshift is not included.
  • The governing TP53 VCEP flowchart and both listed lookup tables were searched under all three supplied variant notations, with no matching entry found.
Still missing
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in PP3-BP4-codes.xlsx.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; this table is additionally limited to in-frame deletions.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
PP5 VCEPNot applicable: the TP53 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel classification for this deletion. Details ▾Hide ▴
Reasoning

The TP53 VCEP explicitly marks PP5 as not applicable and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The case also has no ClinVar record or expert-panel classification for this exact variant.

VCEP rule
TP53 VCEP PP5: not applicable; do not use.
Evidence considered
  • The TP53 VCEP marks PP5 Not Applicable and says the criterion is not for use.
  • ClinVar returned no exact record for NM_000546.6:c.997_1006del.
Sources
cspec ↗clinvar ↗
BS3 N/ANot applicable: no BS3 assignment exists for this frameshift, and the governing worksheet's R333 results are missense substitutions rather than p.Arg333SerfsTer9. Details ▾Hide ▴
Reasoning

The TP53 VCEP functional framework explicitly covers missense variants and small in-frame deletions, and its BS3 rule requires functional or partially functional assay results in the specified assay framework. This variant is a frameshift, NM_000546.6:c.997_1006del, producing p.(Arg333SerfsTer9), not a missense or in-frame deletion. The authoritative Functional-worksheet.xlsx contains no exact entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9; the R333 entries are missense substitutions and cannot establish benign functional evidence for this frameshift. Therefore BS3 is not applicable.

Rule
TP53 VCEP BS3: functional on Kato data and no loss of function by the majority of available eligible assays; BS3_Supporting may also apply to small deletions with available Kotler data that are loss of function by the majority of available assays.
Evidence considered
  • The TP53 VCEP BS3 rule requires functional or partially functional results under the specified assay framework and includes a small-deletion provision only where the stated assay evidence is available.
  • The exact notations c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9 were searched in both governing functional files with no match; the worksheet's R333 rows are missense substitutions only.
  • PMID:16007150 evaluates R333 missense substitutions in oligomerization and transactivation assays, not the queried frameshift, so it cannot support BS3 for this variant.
Still missing
  • No exact entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Flowchart-for-application-of-functional-rule-codes.pdf.txt.
  • No exact entry for c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 was found in Functional-worksheet.xlsx.txt; R333 entries there are missense substitutions only.
  • No variant-specific functional assay demonstrating preserved function for this frameshift was identified in the consulted paper extracts.
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:16007150 ↗
BP1 VCEPNot applicable: the TP53 VCEP excludes BP1, and c.997_1006del is a truncating frameshift. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP explicitly states that BP1 is not applicable to TP53 because truncating variants account for only a portion of disease-causing variants. The queried variant is a truncating frameshift, so BP1 cannot be applied.

VCEP rule
BP1 is not applicable under the TP53 VCEP specification.
Evidence considered
  • The TP53 VCEP BP1 instruction states that BP1 does not apply because truncating variants account for only a portion of disease-causing TP53 variants.
Sources
cspec ↗
BP2 VCEPNot applicable: TP53 VCEP version 2.4 explicitly designates BP2 as not applicable for this disorder. Details ▾Hide ▴
Reasoning

The ClinGen TP53 Expert Panel Specifications, version 2.4, explicitly designate BP2 as not applicable. Because the governing TP53 framework excludes this criterion, observations of the variant in cis with a pathogenic variant or in trans with a benign variant are not used for BP2 in this case.

VCEP rule
Not Applicable
Evidence considered
  • The TP53 Expert Panel ACMG/AMP Specifications, version 2.4, list BP2 as not applicable.
  • The governing specification excludes BP2 regardless of available phase or allelic observations.
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 is restricted to in-frame changes in repetitive regions, whereas this variant is a TP53 protein-truncating frameshift. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the TP53 VCEP v2.4 specification. BP3 concerns in-frame deletions or insertions in repetitive regions without known function; this variant is a protein-truncating frameshift and does not meet that consequence definition.

VCEP rule
TP53 VCEP v2.4: BP3 is not applicable.
Evidence considered
  • The TP53 VCEP v2.4 specification explicitly lists BP3 as not applicable and describes the underlying ACMG concept as in-frame deletions or insertions in repetitive regions without known function.
  • The normalized variant consequence is frameshift, producing p.(Arg333SerfsTer9), not an in-frame deletion or insertion.
Sources
cspec ↗
BP4 N/ANot applicable: this variant is a frameshift, outside TP53 VCEP BP4 scope for missense, splice-region/intronic, and single-amino-acid in-frame deletion variants. Details ▾Hide ▴
Reasoning

Not applicable. NM_000546.6:c.997_1006del produces the frameshift p.(Arg333SerfsTer9), p.(R333Sfs*9), and is outside the TP53 VCEP BP4 scope for missense variants, splice-region/intronic variants, and specified single-amino-acid in-frame deletions. The TP53 VCEP in-silico materials were searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no entry was found in the PP3-BP4 lookup table, the PP3/BP4/BP7 flowchart text, or the single-amino-acid deletion BayesDel table. Because the variant is a truncating frameshift, SpliceAI, REVEL, and BayesDel were not evaluated for BP4.

Evidence considered
  • The case normalization identifies NM_000546.6:c.997_1006del as a frameshift producing p.(Arg333SerfsTer9) / p.(R333Sfs*9).
  • The TP53 VCEP BP4 rule specifies missense, single-amino-acid in-frame deletion, silent, or intronic contexts; a frameshift is not included.
  • The governing TP53 VCEP flowchart and both listed lookup tables were searched under all three supplied variant notations, with no matching entry found.
Still missing
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in PP3-BP4-codes.xlsx.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; this table is additionally limited to in-frame deletions.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP5 VCEPNot applicable: the TP53 VCEP explicitly designates BP5 as not applicable and provides no governing BP5 rule. Details ▾Hide ▴
Reasoning

The TP53 VCEP explicitly marks BP5 as not applicable, with no TP53-specific rule for applying this criterion. Therefore BP5 is not applicable regardless of the absence of an alternate molecular diagnosis in the supplied case evidence.

VCEP rule
TP53 VCEP BP5: not applicable.
Evidence considered
  • The TP53 VCEP marks BP5 Not Applicable and provides no applicable strength rule beyond that designation.
Sources
cspec ↗
BP6 VCEPNot applicable: the TP53 VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel benign classification for this deletion. Details ▾Hide ▴
Reasoning

The TP53 VCEP explicitly marks BP6 as not applicable and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The case also has no ClinVar record or exact-variant expert-panel benign or likely-benign classification.

VCEP rule
TP53 VCEP BP6: not applicable; do not use.
Evidence considered
  • The TP53 VCEP marks BP6 Not Applicable and says the criterion is not for use.
  • ClinVar returned no exact record for NM_000546.6:c.997_1006del, so no expert-panel benign or likely-benign classification exists in the supplied ClinVar result.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: this variant is a frameshift, whereas TP53 VCEP BP7 applies only to synonymous or intronic variants. Details ▾Hide ▴
Reasoning

Not applicable. NM_000546.6:c.997_1006del is a frameshift, not a synonymous variant or an intronic variant, so it is outside the TP53 VCEP BP7 scope. The TP53 VCEP PP3/BP4/BP7 flowchart was searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no entry was found. SpliceAI was not evaluated because BP7 is upstream inapplicable for this consequence type.

Evidence considered
  • The case normalization identifies NM_000546.6:c.997_1006del as a frameshift producing p.(Arg333SerfsTer9) / p.(R333Sfs*9).
  • The TP53 VCEP BP7 rule applies to synonymous or intronic variants, not frameshift variants.
  • The governing TP53 PP3/BP4/BP7 flowchart was searched under all three supplied variant notations, with no matching entry found.
Still missing
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.997_1006del
Protein (HGVS p.)
NP_000537.3:p.(Arg333SerfsTer9)
GRCh38
chr17:7670702 TCACGCCCACG>T
GRCh37
chr17:7574020 TCACGCCCACG>T
Location and type
Exon 10 · frameshift

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…
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

Pangolin splice lossmagnitude shown
-0.051
Pangolin splice gain
0.049

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: this variant is a frameshift, outside TP53 VCEP PP3 scope for missense, splice-region/intronic, and single-amino-acid in-frame deletion variants. Details ▾Hide ▴
Reasoning

Not applicable. NM_000546.6:c.997_1006del produces the frameshift p.(Arg333SerfsTer9), p.(R333Sfs*9), and is therefore outside the TP53 VCEP PP3 scope for missense variants, splice-region/intronic variants, and specified single-amino-acid in-frame deletions. The TP53 VCEP in-silico materials were searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no entry was found in the PP3-BP4 lookup table, the PP3/BP4/BP7 flowchart text, or the single-amino-acid deletion BayesDel table. Because the variant is a truncating frameshift, SpliceAI, REVEL, and BayesDel were not evaluated for PP3.

Evidence considered
  • The case normalization identifies NM_000546.6:c.997_1006del as a frameshift producing p.(Arg333SerfsTer9) / p.(R333Sfs*9).
  • The TP53 VCEP PP3 rule specifies missense, single-amino-acid in-frame deletion, exonic splice-effect, or intronic splice-variant contexts; a frameshift is not included.
  • The governing TP53 VCEP flowchart and both listed lookup tables were searched under all three supplied variant notations, with no matching entry found.
Still missing
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in PP3-BP4-codes.xlsx.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; this table is additionally limited to in-frame deletions.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP4 N/ANot applicable: this variant is a frameshift, outside TP53 VCEP BP4 scope for missense, splice-region/intronic, and single-amino-acid in-frame deletion variants. Details ▾Hide ▴
Reasoning

Not applicable. NM_000546.6:c.997_1006del produces the frameshift p.(Arg333SerfsTer9), p.(R333Sfs*9), and is outside the TP53 VCEP BP4 scope for missense variants, splice-region/intronic variants, and specified single-amino-acid in-frame deletions. The TP53 VCEP in-silico materials were searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no entry was found in the PP3-BP4 lookup table, the PP3/BP4/BP7 flowchart text, or the single-amino-acid deletion BayesDel table. Because the variant is a truncating frameshift, SpliceAI, REVEL, and BayesDel were not evaluated for BP4.

Evidence considered
  • The case normalization identifies NM_000546.6:c.997_1006del as a frameshift producing p.(Arg333SerfsTer9) / p.(R333Sfs*9).
  • The TP53 VCEP BP4 rule specifies missense, single-amino-acid in-frame deletion, silent, or intronic contexts; a frameshift is not included.
  • The governing TP53 VCEP flowchart and both listed lookup tables were searched under all three supplied variant notations, with no matching entry found.
Still missing
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in PP3-BP4-codes.xlsx.txt.
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; this table is additionally limited to in-frame deletions.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP7 N/ANot applicable: this variant is a frameshift, whereas TP53 VCEP BP7 applies only to synonymous or intronic variants. Details ▾Hide ▴
Reasoning

Not applicable. NM_000546.6:c.997_1006del is a frameshift, not a synonymous variant or an intronic variant, so it is outside the TP53 VCEP BP7 scope. The TP53 VCEP PP3/BP4/BP7 flowchart was searched for c.997_1006del, p.Arg333SerfsTer9, and p.R333Sfs*9; no entry was found. SpliceAI was not evaluated because BP7 is upstream inapplicable for this consequence type.

Evidence considered
  • The case normalization identifies NM_000546.6:c.997_1006del as a frameshift producing p.(Arg333SerfsTer9) / p.(R333Sfs*9).
  • The TP53 VCEP BP7 rule applies to synonymous or intronic variants, not frameshift variants.
  • The governing TP53 PP3/BP4/BP7 flowchart was searched under all three supplied variant notations, with no matching entry found.
Still missing
  • No c.997_1006del, p.Arg333SerfsTer9, or p.R333Sfs*9 entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

5 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

  • A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
    No paper-specific finding is recorded.
    PMID 11753428 ↗
  • Rescuing the function of mutant p53.
    No paper-specific finding is recorded.
    PMID 11900253 ↗
  • The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.
    This study evaluates TP53 missense substitutions in the tetramerization domain, including residue R333, but does not mention the queried c.997_1006del frameshift or establish a qualifying pathogenic or likely pathogenic comparator for PM5.
    Does not name this variant
    PMID 16007150 ↗
    Quoted passage
    Among the mutants in these residues, six (R333P, R342P, E349K and E349V) were monomer mutants, indicating that R333, R342 and E349 may contribute to monomer–monomer interaction.

    Results, paragraph discussing residues R333, R342, E343, E346, E349, K351, A353 and Q354

  • High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.
    No paper-specific finding is recorded.
    PMID 19336573 ↗
  • Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.
    No paper-specific finding is recorded.
    PMID 21467160 ↗

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 Captured ClinVar source record 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

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 returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.