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TP53c.574C>TLikely pathogenic
Print report
Variant interpretation report

TP53 c.574C>T, p.(Gln192Ter)

NM_000546.6:c.574C>T NP_000537.3:p.(Gln192Ter) Nonsense · exon 6 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: TP53 p.Gln192Ter creates a premature stop at codon 192, upstream of p.Lys351, meeting the VCEP NMD PVS1 rule.

PM2Supporting
PM2 · supporting

Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed frequency 0 versus the TP53 VCEP PM2 threshold <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) plus PM2 (supporting) total 9 points under the ClinGen TP53 Expert Panel's 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
7 reported laboratory submissions

6 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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
267 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52660737, n = 267 times).

Cancer Hotspots

This variant lies 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 · 8 not assessed · 16 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

All five requested codon/residue/domain criteria are not applicable under the governing TP53 VCEP framework because the assessed variant is the nonsense change NM_000546.6:c.574C>T, p.(Gln192Ter), rather than a missense substitution; PP2 and BP1 are additionally explicitly excluded by the VCEP.

The governing TP53 VCEP Version 2.4 framework was used for PS2, PM6, PP1, and BS4.

PS2, PP1, and BS4 remain not assessed because the case evidence does not document the family, parental, phenotype, genotype, or meiosis data required for these criteria; PM6 is not applicable under the TP53 VCEP.

The searched VCEP LFS cancer and point table contains no variant-specific entry for c.574C>T, p.Gln192Ter, or p.Q192*; it supplies the governing phenotype point definitions and PS2 thresholds rather than case observations.

Population evidence supports PM2 at supporting strength because the variant is absent from gnomAD v2.1 and v4.1.

BA1 and BS1 are not met because no frequency reaches their TP53 VCEP thresholds.

BS2 is not assessed because qualifying age-, sex-, cancer-status-, source-, and sarcoma-specific unaffected-carrier counts are unavailable.

Met · 2

PVS1 Very strongMet, very strong: TP53 p.Gln192Ter creates a premature stop at codon 192, upstream of p.Lys351, meeting the VCEP NMD PVS1 rule. Details ▾Hide ▴
Reasoning

NM_000546.6:c.574C>T is a TP53 nonsense variant, NP_000537.3:p.(Gln192Ter)/p.(Q192*), in exon 6. The premature termination codon at codon 192 is upstream of p.Lys351, so the TP53 VCEP PVS1 flowchart classifies this as predicted to undergo nonsense-mediated decay and assigns full PVS1. The transcript is the governing biologically relevant transcript NM_000546.6, and the predicted product retains only 192 of 394 amino acids, supporting a null consequence. The exact variant was not found as a variant-specific entry in PVS1-Flowchart.pdf; that file provides the applicable rule rather than a per-variant table. The exact variant was not found in PVS1-Splicing-Worksheet.xlsx; that worksheet is for canonical splice-site variants and is not applicable to this exonic nonsense variant.

Rule
TP53 VCEP PVS1 flowchart: nonsense upstream of p.Lys351 and predicted to undergo NMD receives full PVS1.
Evidence considered
  • The case normalization identifies NM_000546.6:c.574C>T as NP_000537.3:p.(Gln192Ter)/p.(Q192*), a nonsense variant in exon 6.
  • The TP53 VCEP PVS1 flowchart states that nonsense variants upstream of p.Lys351 predicted to undergo NMD receive PVS1.
  • The predicted protein ends at amino acid 192 instead of the normal 394 amino acids, consistent with a premature truncation well upstream of the TP53 C-terminal threshold.
  • Exact-notation searches for c.574C>T, p.Gln192Ter, and p.Q192* found no variant-specific row in the PVS1 flowchart or the splice-site worksheet; the worksheet is not applicable to this exonic nonsense change.
Still missing
  • No variant-specific entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PVS1-Flowchart.pdf; the governing flowchart rule was applicable.
  • No variant-specific entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PVS1-Splicing-Worksheet.xlsx; this worksheet covers canonical splice-site variants, not exonic nonsense variants.
Sources
cspec ↗vcep_pvs1_flowchart
PM2 SupportingMet at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed frequency 0 versus the TP53 VCEP PM2 threshold <0.00003. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires PM2 at supporting strength when the variant allele frequency is <0.00003 (0.003%) in gnomAD or another large sequenced population; if multiple alleles are present within an ancestry group, that group's frequency must be <0.00004 (0.004%). The variant is absent from gnomAD v2.1 and v4.1, so its observed frequency is 0 in these datasets and below both VCEP thresholds. PM2_Supporting is met. The VCEP's possible allele-balance recalculation for clonal hematopoiesis is not needed because the recorded frequency is absence rather than a low positive frequency.

Rule
Apply PM2 at supporting level when allele frequency is <0.00003 (0.003%) in gnomAD or another large sequenced population; if multiple alleles are present within any genetic ancestry group, that group's allele frequency must be <0.00004 (0.004%). Ignore founder-effect ancestry groups.
Evidence considered
  • The TP53 VCEP specifies PM2 at supporting strength for allele frequency <0.00003 (0.003%) and, when multiple alleles are present in an ancestry group, frequency <0.00004 (0.004%); founder-effect ancestry groups are excluded.
  • The variant is reported as absent from gnomAD v2.1 and gnomAD v4.1, giving an observed frequency of 0 in both queried population datasets and satisfying the VCEP PM2 threshold.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 2 · evaluated, threshold not reached

BA1 Not met: gnomAD v2.1 and v4.1 report absence, not a TP53 VCEP BA1 filtering allele frequency >=0.001 in one eligible ancestry group. Details ▾Hide ▴
Reasoning

The TP53 NM_000546.6:c.574C>T, p.(Gln192Ter) variant is absent from gnomAD v2.1 and gnomAD v4.1. Therefore, no continental-subpopulation filtering allele frequency is available that reaches the TP53 VCEP BA1 threshold of >=0.001 (0.1%) in a single eligible ancestry group with at least 2,000 alleles tested and at least 2 variant alleles. BA1 is not met.

Rule
Filtering allele frequency (FAF) >= 0.001 or 0.1% in a gnomAD continental subpopulation of a single eligible genetic ancestry group, with >=2,000 alleles tested and a minimum of 2 alleles present.
Evidence considered
  • The TP53 VCEP specifies BA1 at stand-alone strength only when filtering allele frequency is >=0.001 (0.1%) in a single eligible continental ancestry group with >=2,000 alleles tested and at least 2 variant alleles.
  • The variant is reported as absent from gnomAD v2.1 and gnomAD v4.1; consequently, the BA1 frequency threshold is not reached.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: gnomAD v2.1 and v4.1 report absence, not a TP53 VCEP BS1 filtering allele frequency from 0.0003 to below 0.001. Details ▾Hide ▴
Reasoning

The TP53 NM_000546.6:c.574C>T, p.(Gln192Ter) variant is absent from gnomAD v2.1 and gnomAD v4.1. No eligible continental-subpopulation filtering allele frequency is available in the TP53 VCEP BS1 interval of >=0.0003 and <0.001, with at least 2,000 alleles tested and at least 2 variant alleles. BS1 is not met.

Rule
Filtering allele frequency (FAF) >= 0.0003 but <0.001 in a gnomAD continental subpopulation of a single eligible genetic ancestry group, with >=2,000 alleles tested and a minimum of 2 alleles present.
Evidence considered
  • The TP53 VCEP specifies BS1 at strong strength when filtering allele frequency is >=0.0003 and <0.001 in a single eligible continental ancestry group with >=2,000 alleles tested and at least 2 variant alleles.
  • The variant is reported as absent from gnomAD v2.1 and gnomAD v4.1; consequently, the BS1 frequency interval is not reached.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 8 · no assessment recorded

PS2 Not assessed: no verified de novo observation, parental testing, or PS2 phenotype points are documented for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies PS2 using de novo observations weighted by the LFS cancer phenotype: 1 point is Supporting, 2-3 points Moderate, 4-7 points Strong, and at least 8 points Very Strong. The available case evidence contains no documented proband phenotype, confirmed maternity and paternity, parental testing, or other verified de novo observation for NM_000546.6:c.574C>T (p.Gln192Ter; p.Q192*), so no PS2 point total or strength can be assigned.

Rule
PS2: Very Strong for ≥8 points; Strong for 4-7 points; Moderate for 2-3 points; Supporting for 1 point.
Evidence considered
  • The TP53 VCEP Version 2.4 rule assigns PS2 strength by total points: Supporting for 1 point, Moderate for 2-3 points, Strong for 4-7 points, and Very Strong for at least 8 points.
  • The governing LFS cancer table assigns 4 points for a strongly associated cancer when maternity and paternity are confirmed, 2 points when they are assumed, 2 points for a moderately associated cancer when maternity and paternity are confirmed, and 1 point when they are assumed.
  • No verified proband phenotype, parental testing, or de novo observation for c.574C>T/p.Gln192Ter/p.Q192* was available in the case evidence reviewed.
Still missing
  • No documented proband cancer phenotype and age for PS2 point assignment.
  • No documented maternity and paternity confirmation status.
  • No parental testing results establishing a de novo occurrence.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* 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
PS3 Not assessed: TP53's functional worksheet has no p.Gln192Ter entry, and no reviewed publication reports a validated functional assay for this exact nonsense variant. Details ▾Hide ▴
Reasoning

The governing TP53 functional flowchart and Functional-worksheet.xlsx define pre-assigned PS3/BS3 results for missense variants and small in-frame deletions. The case variant is the nonsense change NM_000546.6:c.574C>T, p.Gln192Ter (p.Q192*), and the worksheet search found no c.574C>T, p.Gln192Ter, or p.Q192* entry; it contains other Q192 missense substitutions only. The reviewed case literature contains no exact-variant functional assay result: PMID:16007150 tested missense variants in residues 322-354, and PMID:21467160 and PMID:19336573 provide only general truncating-TP53 context. Therefore, no validated variant-specific functional evidence meets a TP53 VCEP PS3 rule, and PS3 is not assessed rather than inferred from the truncating consequence or another criterion.

Evidence considered
  • The TP53 VCEP v2.4 PS3 rule requires non-functional Kato data plus loss of function by the majority of other eligible assays, or specified supporting pathways; the functional flowchart identifies Kato, Funk, Giacomelli, Kotler, and Kawaguchi as eligible studies.
  • The full Functional-worksheet.xlsx text was searched for c.574C>T, p.Gln192Ter, and p.Q192*; no exact variant row was found. Q192A, Q192D, Q192E, Q192G, Q192H, Q192K, Q192L, Q192N, Q192P, Q192R, Q192S, Q192T, Q192V, Q192W, and Q192Y are different missense substitutions and cannot establish PS3 for p.Q192*.
  • PMID:16007150 studied 184 missense mutants in the C-terminal tetramerization domain, not the truncating p.Q192* variant.
  • PMID:19336573 and PMID:21467160 describe TP53 truncating mutations as a class but do not report a functional assay result for c.574C>T or p.Q192*.
Still missing
  • Flowchart-for-application-of-functional-rule-codes.pdf: no entry for c.574C>T, p.Gln192Ter, or p.Q192*; the file provides the governing framework but no variant-specific result.
  • Functional-worksheet.xlsx: no entry for c.574C>T, p.Gln192Ter, or p.Q192*; only other Q192 missense substitutions were found.
  • No exact-variant functional assay result was available in the reviewed case literature.
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:16007150 ↗PMID:19336573 ↗PMID:21467160 ↗
PS4 Not assessed: the PS4 point total is unavailable, so the VCEP thresholds of 1-1.5, 2-3.5, 4-7.5, or >=8 points cannot be applied. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies PS4 using proband point totals: the governing PS4-Points-Table assigns 0.5 point for Revised Chompret, 1 point for Classic LFS criteria, and 0.5 point for an unrelated proband with HER2-positive breast cancer diagnosed below age 40; strength is Supporting at 1-1.5 points, Moderate at 2-3.5, Strong at 4-7.5, and Very Strong at >=8. The case evidence does not provide patient-level cancer phenotype, age, HER2 status, Chompret/Classic LFS status, or a PS4 point total, so no governing PS4 strength can be assigned. Searches of PS4-Points-Table.pdf.txt for c.574C>T, p.Gln192Ter, and p.Q192* found no exact-variant entry; this is a gap in that file, not evidence that PS4 evidence is absent.

Rule
VCEP PS4: 0.5 point for Revised Chompret, 1 point for Classic LFS criteria, or 0.5 point for unrelated HER2-positive breast cancer diagnosed below age 40; Supporting = 1-1.5 points, Moderate = 2-3.5 points, Strong = 4-7.5 points, Very Strong >=8 points.
Evidence considered
  • The TP53 VCEP PS4 rule states that Revised Chompret contributes 0.5 point, Classic LFS contributes 1 point, and HER2-positive breast cancer diagnosed below age 40 contributes 0.5 point for an unrelated proband.
  • The governing PS4 strength thresholds are Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, and Very Strong >=8 points.
  • The case evidence reviewed contains no patient-level phenotype or PS4 point tally for this variant.
  • PS4-Points-Table.pdf.txt was searched for c.574C>T, p.Gln192Ter, and p.Q192*; no exact-variant entry was found.
Still missing
  • Patient-level cancer phenotype, age at diagnosis, HER2 status, and whether Revised Chompret or Classic LFS criteria are met are not available.
  • The PS4 point total per proband and across probands is not available.
  • No exact-variant entry was found in PS4-Points-Table.pdf.txt after searching c.574C>T, p.Gln192Ter, and p.Q192*.
Sources
cspec ↗vcep_ps4_points_table
PP1 Not assessed: no affected-relative genotypes or verified cosegregating meioses are documented for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires cosegregation in 3-4 meioses for PP1 Supporting, 5-6 meioses for PP1 Moderate, and at least 7 meioses across more than one family for PP1 Strong. The available case evidence contains no verified affected relatives, genotypes, family structure, or meiosis count for NM_000546.6:c.574C>T (p.Gln192Ter; p.Q192*), so PP1 cannot be assigned.

Rule
PP1: Supporting for 3-4 cosegregating meioses; Moderate for 5-6 meioses; Strong for ≥7 meioses across >1 family.
Evidence considered
  • The TP53 VCEP requires 3-4 cosegregating meioses for PP1 Supporting, 5-6 for PP1 Moderate, and at least 7 cosegregating meioses across more than one family for PP1 Strong.
  • The governing LFS cancer table defines the LFS-associated cancer types used for PS2 and PP1 code application.
  • No verified affected-relative phenotype, relative genotype, family segregation result, or meiosis count for c.574C>T/p.Gln192Ter/p.Q192* was available in the case evidence reviewed.
Still missing
  • No documented affected relatives with LFS-associated cancers and ages.
  • No genotype results for informative relatives.
  • No family structure or verified meiosis count.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* 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: no qualifying TP53 VAF observation is documented, so the VCEP thresholds of 5-25% or 5-35% cannot be applied. Details ▾Hide ▴
Reasoning

The TP53 VCEP PP4 rule is applicable to low-variant-allele-fraction TP53 findings in multigene-panel testing: at least 2 independent observations with VAF 5-25% support PP4 at Moderate, and an observation with VAF 5-35% supports PP4 at Supporting. The case evidence does not document qualifying VAF observations, multigene-panel testing, blood-source context, or whether the variant is constitutional mosaicism/CHIP; therefore PP4 cannot be assessed. PP4 is also phenotype-based evidence that must not be combined with PS4, PS2, or PP1 in the same individual under the VCEP caveat.

Rule
VCEP PP4: Moderate for at least 2 independent observations with VAF 5-25%; Supporting for an observation with VAF 5-35%, with the stated TP53 low-VAF and multigene-panel caveats.
Evidence considered
  • The TP53 VCEP PP4 rule requires at least 2 independent observations with VAF 5-25% for Moderate or an observation with VAF 5-35% for Supporting.
  • The case evidence does not provide VAF values or the required testing and clinical context.
  • The VCEP states that PP4 and phenotype-based PS4, PS2, or PP1 points cannot be applied in combination for the same individual.
Still missing
  • Number of independent observations and exact VAF values are not available.
  • Testing context, including multigene-panel testing and blood-source status, is not available.
  • Constitutional mosaicism, clonal hematopoiesis, blood cancer, and alternative cancer-predisposition causes are not documented.
Sources
cspec ↗
BS2 Not assessed: no single-source count of at least two unrelated unaffected females aged 60 or older is available for the TP53 VCEP BS2 rule. Details ▾Hide ▴
Reasoning

The available population evidence reports only that the variant is absent from gnomAD v2.1 and v4.1. It does not provide a count of unrelated unaffected females who reached at least 60 years of age without cancer from one source, nor does it provide the TP53 VCEP-required review of sarcoma diagnoses. The BS2 threshold cannot be evaluated.

Rule
BS2 Supporting requires 2-3 unrelated females from one source who have reached at least 60 years of age without cancer; individuals with sarcoma diagnosed at age >=61 years must not be counted.
Evidence considered
  • The TP53 VCEP requires at least 2 unrelated females from one source who reached at least 60 years of age without cancer for BS2 Supporting, with higher strengths requiring 4-7 or at least 8 qualifying individuals.
  • The available gnomAD records report variant absence but do not identify unaffected female carriers, ages, cancer status, source-specific counts, or sarcoma exclusions.
Still missing
  • A single-source cohort or database count of unrelated females who reached at least 60 years of age without cancer is unavailable.
  • The required exclusion of individuals with sarcoma diagnosed at age 61 or older cannot be verified.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 Not assessed: no exact p.Gln192Ter functional result was found in the governing TP53 worksheet or reviewed literature to demonstrate retained function. Details ▾Hide ▴
Reasoning

The governing TP53 functional flowchart and Functional-worksheet.xlsx define pre-assigned PS3/BS3 results for missense variants and small in-frame deletions. The case variant is the nonsense change NM_000546.6:c.574C>T, p.Gln192Ter (p.Q192*), and the worksheet search found no c.574C>T, p.Gln192Ter, or p.Q192* entry; it contains other Q192 missense substitutions only. The reviewed case literature contains no exact-variant functional assay demonstrating retained function or absence of loss of function. Therefore, BS3 cannot be applied or excluded from a variant-specific assay result and is not assessed.

Evidence considered
  • The TP53 VCEP v2.4 BS3 rule requires functional Kato data plus no loss of function by the majority of eligible assays, or the specified supporting pathway; no such exact-variant data were identified.
  • The full Functional-worksheet.xlsx text was searched for c.574C>T, p.Gln192Ter, and p.Q192*; no exact variant row was found. Results for different Q192 missense substitutions cannot establish BS3 for p.Q192*.
  • PMID:16007150 studied missense mutants in residues 322-354, while PMID:19336573 and PMID:21467160 describe truncating TP53 mutations generally without an exact p.Q192* functional assay.
Still missing
  • Flowchart-for-application-of-functional-rule-codes.pdf: no entry for c.574C>T, p.Gln192Ter, or p.Q192*; the file provides the governing framework but no variant-specific result.
  • Functional-worksheet.xlsx: no entry for c.574C>T, p.Gln192Ter, or p.Q192*; only other Q192 missense substitutions were found.
  • No exact-variant functional assay result was available in the reviewed case literature.
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:16007150 ↗PMID:19336573 ↗PMID:21467160 ↗
BS4 Not assessed: no affected family members with verified non-segregation or genotype results are documented. Details ▾Hide ▴
Reasoning

The TP53 VCEP permits BS4 Strong for lack of segregation in affected family members diagnosed with LFS-associated cancers. The available case evidence contains no verified affected family members, their genotypes, or non-segregation results for NM_000546.6:c.574C>T (p.Gln192Ter; p.Q192*), so BS4 cannot be assessed.

Rule
BS4: Strong for lack of segregation in affected family members diagnosed with LFS-associated cancers.
Evidence considered
  • The TP53 VCEP defines BS4 Strong as lack of segregation in affected family members diagnosed with LFS-associated cancers.
  • The governing LFS cancer table provides the LFS-associated cancer categories relevant to family segregation assessment.
  • No verified affected-family-member genotypes or non-segregation result for c.574C>T/p.Gln192Ter/p.Q192* was available in the case evidence reviewed.
Still missing
  • No documented affected family members meeting the TP53 VCEP LFS-associated cancer definition.
  • No family-member genotype results showing the variant is absent.
  • No verified non-segregation analysis.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* 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 · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: p.(Gln192Ter) is a nonsense variant, not an amino-acid substitution eligible for the TP53 VCEP PS1 rule. Details ▾Hide ▴
Reasoning

The TP53 VCEP framework permits PS1 for a variant with the same amino-acid change as a pathogenic or likely pathogenic variant, but this case is NM_000546.6:c.574C>T, p.(Gln192Ter), a nonsense variant rather than an amino-acid substitution. PS1 therefore cannot be applied to this variant.

Rule
TP53 VCEP PS1: can be applied to variants asserted as Pathogenic or Likely Pathogenic following the TP53 VCEP specifications.
Evidence considered
  • The TP53 VCEP Version 2.4 specification defines PS1 for variants asserted as pathogenic or likely pathogenic under its specifications; the case variant is p.(Gln192Ter), a nonsense consequence.
Sources
cspec ↗
PM1 N/ANot applicable: p.(Gln192Ter) is nonsense, while the TP53 VCEP PM1 rule requires a missense variant in an approved codon or hotspot. Details ▾Hide ▴
Reasoning

The TP53 VCEP PM1 rule is restricted to missense variants in specified critical codons or to germline missense variants observed in cancerhotspots.org with the required same-amino-acid somatic count. This case variant is the nonsense change p.(Gln192Ter), not a missense variant. The authoritative vcep_materials.json domain_tables entry for TP53 is empty, so no approved domain interval adds an alternative PM1 route.

Rule
TP53 VCEP PM1: missense variants at codons 175, 245, 248, 249, 273, or 282; alternatively, qualifying germline missense variants in cancerhotspots.org with the specified same-amino-acid somatic occurrence count.
Evidence considered
  • The TP53 VCEP Version 2.4 PM1 rule specifies missense variants at codons 175, 245, 248, 249, 273, or 282, or qualifying germline missense hotspot changes.
  • The authoritative vcep_materials.json domain_tables object contains no TP53 domain entries; the variant consequence remains nonsense and cannot satisfy the missense-based PM1 rule.
Sources
cspec ↗vcep_output
PM3 VCEPNot applicable: the TP53 VCEP explicitly excludes PM3 for autosomal-dominant Li-Fraumeni syndrome. Details ▾Hide ▴
Reasoning

The governing ClinGen TP53 Expert Panel specification, version 2.4, explicitly marks PM3 as not applicable to TP53/Li-Fraumeni syndrome. PM3 is a recessive-disease criterion requiring a variant in trans with a pathogenic variant, whereas Li-Fraumeni syndrome is autosomal dominant; therefore phase or affected-proband observations cannot activate PM3 under this framework.

VCEP rule
This rule does not apply to TP53/Li-Fraumeni syndrome.
Evidence considered
  • The TP53 VCEP version 2.4 criterion specification states that PM3 is not applicable and specifically says the rule does not apply to TP53/Li-Fraumeni syndrome.
  • The governing framework identifies Li-Fraumeni syndrome as autosomal dominant, so recessive in-trans evidence is not used for PM3 here.
Sources
cspec ↗
PM4 VCEPNot applicable: p.Gln192Ter is a nonsense substitution, not an in-frame indel or other PM4-eligible protein-length change. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the TP53 VCEP specification. This variant is a nonsense single-nucleotide substitution producing p.(Gln192Ter), not an in-frame indel or other protein-length change for which PM4 would be considered. The TP53 VCEP explicitly lists PM4 as not applicable.

VCEP rule
TP53 VCEP PM4 applicability: not applicable.
Evidence considered
  • The TP53 VCEP specification marks PM4 as not applicable.
  • The normalized consequence is a nonsense substitution, NM_000546.6:c.574C>T, rather than an in-frame deletion, insertion, or indel.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 requires a missense variant, but this case is the nonsense change p.(Gln192Ter). Details ▾Hide ▴
Reasoning

The TP53 VCEP PM5 framework is a same-residue missense rule: it requires the assessed variant to be a missense variant and counts different missense variants at that residue with VCEP-determined pathogenic or likely pathogenic classifications. The assessed variant is p.(Gln192Ter), a nonsense variant, so PM5 does not apply.

Rule
TP53 VCEP PM5: apply at the specified strength when a missense variant has one or more different missense variants at the same residue previously determined pathogenic or likely pathogenic under the TP53 VCEP specifications.
Evidence considered
  • The TP53 VCEP PM5 rule requires a missense variant at an amino-acid residue with qualifying previously observed missense variants.
  • The case comparator assessment identified no eligible PM5 candidates because the assessed consequence is nonsense, not missense.
Sources
cspec ↗pm5_candidates
PM6 VCEPNot applicable: the TP53 VCEP explicitly designates PM6 as not applicable. Details ▾Hide ▴
Reasoning

The TP53 VCEP Version 2.4 explicitly lists PM6 as not applicable. Therefore, assumed de novo status without confirmed parental testing cannot be applied under the governing gene-specific framework.

VCEP rule
PM6: Not applicable under the TP53 VCEP Version 2.4 specification.
Evidence considered
  • The TP53 VCEP Version 2.4 specification lists PM6 applicability as Not Applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the TP53 VCEP explicitly excludes PP2, and this case variant is nonsense rather than missense. Details ▾Hide ▴
Reasoning

The TP53 VCEP Version 2.4 framework explicitly marks PP2 as not applicable. In addition, the generic PP2 concept concerns missense variation in a gene with a high proportion of pathogenic missense variants, whereas this case variant is nonsense p.(Gln192Ter).

VCEP rule
TP53 VCEP PP2: Not Applicable.
Evidence considered
  • The TP53 VCEP Version 2.4 specification lists PP2 as not applicable; the assessed variant is p.(Gln192Ter), a nonsense consequence.
Sources
cspec ↗
PP3 N/ANot applicable: p.(Gln192Ter) is a nonsense variant, outside the TP53 VCEP PP3 scope for missense, deletion, and splice-impact variants. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_000546.6:c.574C>T produces the nonsense consequence p.(Gln192Ter)/p.(Q192*), whereas the TP53 VCEP PP3 specification covers missense variants, selected in-frame deletions, and exonic or intronic splice-impact variants, not truncating nonsense variants. The governing TP53 PP3/BP4/BP7 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched under c.574C>T, p.Gln192Ter, and p.Q192*; no entry for this variant was found, but predictor scores were not evaluated because the criterion is out of scope.

Rule
TP53 VCEP PP3 applies to specified missense, single-amino-acid in-frame deletion, or splice-impact variants; nonsense variants are outside scope.
Evidence considered
  • The TP53 CSPEC version 2.4 identifies PP3 as applicable to missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants, with no nonsense-variant pathway.
  • The TP53 VCEP flowchart and both governing converted lookup tables were searched for c.574C>T, p.Gln192Ter, and p.Q192*; no matching entry was found.
  • The case normalization identifies NM_000546.6:c.574C>T as the nonsense variant NP_000537.3:p.(Gln192Ter), also p.(Q192*).
Still missing
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PP3-BP4-codes.xlsx.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
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 disallows PP5, and ClinVar shows no exact-variant expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks PP5 as not applicable and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Independently, the exact-variant ClinVar record has no expert-panel submission; it reports laboratory submissions only, including Pathogenic and Likely pathogenic classifications. Therefore the required exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification is not present.

VCEP rule
PP5 is not applicable under the TP53 VCEP; outside that prohibition, PP5 would require an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
  • The TP53 VCEP PP5 specification says this criterion is not for use.
  • ClinVar variation 406579 is an exact match but lists zero expert-panel submissions and only laboratory submissions.
Sources
cspec ↗clinvar ↗
BP1 VCEPNot applicable: the TP53 VCEP explicitly excludes BP1, and this case variant is nonsense rather than missense. Details ▾Hide ▴
Reasoning

The TP53 VCEP Version 2.4 framework explicitly marks BP1 as not applicable. The generic BP1 concept is also directed at missense variants in a gene where loss of function is the established disease mechanism; this case variant is a nonsense change, not a missense variant, and the governing VCEP exclusion controls.

VCEP rule
TP53 VCEP BP1: Not Applicable.
Evidence considered
  • The TP53 VCEP Version 2.4 specification lists BP1 as not applicable; the assessed variant is p.(Gln192Ter), a nonsense consequence.
Sources
cspec ↗
BP2 VCEPNot applicable: the TP53 VCEP marks BP2 as not applicable despite describing trans-phase observation scenarios. Details ▾Hide ▴
Reasoning

The governing ClinGen TP53 Expert Panel specification, version 2.4, explicitly marks BP2 as not applicable for this TP53/Li-Fraumeni syndrome framework. Although its detailed text describes phase-confirmed trans observations or repeated observations with different pathogenic or likely pathogenic TP53 variants, the criterion's governing applicability is not applicable; those phase and allelic observations therefore cannot activate BP2 in this adjudication.

VCEP rule
The TP53 VCEP specifies BP2 as not applicable.
Evidence considered
  • The TP53 VCEP version 2.4 criterion specification marks BP2 as not applicable.
  • The same specification describes phase-confirmed trans observations and multiple different pathogenic or likely pathogenic TP53 observations as the BP2 scenario, but those instructions do not override the criterion's not-applicable designation in the governing framework.
Sources
cspec ↗
BP3 VCEPNot applicable: p.Gln192Ter is a premature-stop nonsense variant, not a benign in-frame deletion within a repetitive region. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the TP53 VCEP specification. This variant is a nonsense substitution causing a premature termination codon, not a small in-frame deletion in a repetitive region with no predicted functional impact. The TP53 VCEP explicitly lists BP3 as not applicable.

VCEP rule
TP53 VCEP BP3 applicability: not applicable.
Evidence considered
  • The TP53 VCEP specification marks BP3 as not applicable.
  • The normalized consequence is a nonsense substitution that truncates TP53 at codon 192, so BP3's in-frame repetitive-region context does not apply.
Sources
cspec ↗
BP4 N/ANot applicable: p.(Gln192Ter) is a nonsense variant, outside the TP53 VCEP BP4 scope for missense, deletion, and splice-impact variants. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_000546.6:c.574C>T produces the nonsense consequence p.(Gln192Ter)/p.(Q192*), whereas the TP53 VCEP BP4 specification covers missense variants, selected in-frame deletions, and silent or intronic variants with applicable computational evidence, not truncating nonsense variants. The governing TP53 PP3/BP4/BP7 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched under c.574C>T, p.Gln192Ter, and p.Q192*; no entry for this variant was found, but predictor scores were not evaluated because the criterion is out of scope.

Rule
TP53 VCEP BP4 applies to specified missense, single-amino-acid in-frame deletion, synonymous, or intronic variants; nonsense variants are outside scope.
Evidence considered
  • The TP53 CSPEC version 2.4 identifies BP4 as applicable to specified missense, single-amino-acid in-frame deletion, synonymous, or intronic variants, with no nonsense-variant pathway.
  • The TP53 VCEP flowchart and both governing converted lookup tables were searched for c.574C>T, p.Gln192Ter, and p.Q192*; no matching entry was found.
  • The case normalization identifies NM_000546.6:c.574C>T as the nonsense variant NP_000537.3:p.(Gln192Ter), also p.(Q192*).
Still missing
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PP3-BP4-codes.xlsx.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
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 marks BP5 as not applicable and supplies no governing BP5 rule. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks BP5 as not applicable and provides no applicable strength rule for it. No benign alternate molecular basis for disease is therefore adjudicated under this TP53 framework.

VCEP rule
BP5 is not applicable under the TP53 VCEP.
Evidence considered
  • The TP53 VCEP BP5 specification lists the criterion as not applicable and gives no applicable rule.
Sources
cspec ↗
BP6 VCEPNot applicable: the TP53 VCEP disallows BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks BP6 as not applicable and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Independently, the exact-variant ClinVar record has no expert-panel submission and contains no expert-panel Benign or Likely benign classification. Laboratory submissions and aggregate ClinVar labels do not qualify for BP6.

VCEP rule
BP6 is not applicable under the TP53 VCEP; outside that prohibition, BP6 would require an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
  • The TP53 VCEP BP6 specification says this criterion is not for use.
  • ClinVar variation 406579 is an exact match but lists zero expert-panel submissions; its available submissions are laboratory assertions rather than expert-panel Benign or Likely benign classifications.
  • Ordinary laboratory submissions and aggregate ClinVar labels were not treated as BP6 evidence.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: p.(Gln192Ter) is a nonsense variant, whereas TP53 VCEP BP7 is restricted to synonymous or intronic variants. Details ▾Hide ▴
Reasoning

BP7 is not applicable because NM_000546.6:c.574C>T produces the nonsense consequence p.(Gln192Ter)/p.(Q192*), not a synonymous or intronic variant. The governing TP53 PP3/BP4/BP7 flowchart was searched under c.574C>T, p.Gln192Ter, and p.Q192*; no entry for this variant was found, and SpliceAI was not evaluated because BP7 is upstream out of scope for a truncating variant.

Rule
TP53 VCEP BP7 applies only to synonymous or intronic variants; nonsense variants are outside scope.
Evidence considered
  • The TP53 CSPEC version 2.4 restricts BP7 to synonymous or intronic variants, with supporting application requiring the specified no-splicing-impact conditions.
  • The TP53 VCEP flowchart and all three declared governing converted full-text files were searched for c.574C>T, p.Gln192Ter, and p.Q192*; no matching entry was found.
  • The case normalization identifies NM_000546.6:c.574C>T as the nonsense variant NP_000537.3:p.(Gln192Ter), also p.(Q192*).
Still missing
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PP3-BP4-codes.xlsx.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.574C>T
Protein (HGVS p.)
NP_000537.3:p.(Gln192Ter)
GRCh38
chr17:7674957 G>A
GRCh37
chr17:7578275 G>A
Location and type
Exon 6 · nonsense
ClinVar
406579
COSMIC
COSV52660737

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
-0.482
Pangolin splice gain
0.008

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 N/ANot applicable: p.(Gln192Ter) is a nonsense variant, outside the TP53 VCEP PP3 scope for missense, deletion, and splice-impact variants. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_000546.6:c.574C>T produces the nonsense consequence p.(Gln192Ter)/p.(Q192*), whereas the TP53 VCEP PP3 specification covers missense variants, selected in-frame deletions, and exonic or intronic splice-impact variants, not truncating nonsense variants. The governing TP53 PP3/BP4/BP7 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched under c.574C>T, p.Gln192Ter, and p.Q192*; no entry for this variant was found, but predictor scores were not evaluated because the criterion is out of scope.

Rule
TP53 VCEP PP3 applies to specified missense, single-amino-acid in-frame deletion, or splice-impact variants; nonsense variants are outside scope.
Evidence considered
  • The TP53 CSPEC version 2.4 identifies PP3 as applicable to missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants, with no nonsense-variant pathway.
  • The TP53 VCEP flowchart and both governing converted lookup tables were searched for c.574C>T, p.Gln192Ter, and p.Q192*; no matching entry was found.
  • The case normalization identifies NM_000546.6:c.574C>T as the nonsense variant NP_000537.3:p.(Gln192Ter), also p.(Q192*).
Still missing
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PP3-BP4-codes.xlsx.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
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: p.(Gln192Ter) is a nonsense variant, outside the TP53 VCEP BP4 scope for missense, deletion, and splice-impact variants. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_000546.6:c.574C>T produces the nonsense consequence p.(Gln192Ter)/p.(Q192*), whereas the TP53 VCEP BP4 specification covers missense variants, selected in-frame deletions, and silent or intronic variants with applicable computational evidence, not truncating nonsense variants. The governing TP53 PP3/BP4/BP7 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched under c.574C>T, p.Gln192Ter, and p.Q192*; no entry for this variant was found, but predictor scores were not evaluated because the criterion is out of scope.

Rule
TP53 VCEP BP4 applies to specified missense, single-amino-acid in-frame deletion, synonymous, or intronic variants; nonsense variants are outside scope.
Evidence considered
  • The TP53 CSPEC version 2.4 identifies BP4 as applicable to specified missense, single-amino-acid in-frame deletion, synonymous, or intronic variants, with no nonsense-variant pathway.
  • The TP53 VCEP flowchart and both governing converted lookup tables were searched for c.574C>T, p.Gln192Ter, and p.Q192*; no matching entry was found.
  • The case normalization identifies NM_000546.6:c.574C>T as the nonsense variant NP_000537.3:p.(Gln192Ter), also p.(Q192*).
Still missing
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PP3-BP4-codes.xlsx.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
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: p.(Gln192Ter) is a nonsense variant, whereas TP53 VCEP BP7 is restricted to synonymous or intronic variants. Details ▾Hide ▴
Reasoning

BP7 is not applicable because NM_000546.6:c.574C>T produces the nonsense consequence p.(Gln192Ter)/p.(Q192*), not a synonymous or intronic variant. The governing TP53 PP3/BP4/BP7 flowchart was searched under c.574C>T, p.Gln192Ter, and p.Q192*; no entry for this variant was found, and SpliceAI was not evaluated because BP7 is upstream out of scope for a truncating variant.

Rule
TP53 VCEP BP7 applies only to synonymous or intronic variants; nonsense variants are outside scope.
Evidence considered
  • The TP53 CSPEC version 2.4 restricts BP7 to synonymous or intronic variants, with supporting application requiring the specified no-splicing-impact conditions.
  • The TP53 VCEP flowchart and all three declared governing converted full-text files were searched for c.574C>T, p.Gln192Ter, and p.Q192*; no matching entry was found.
  • The case normalization identifies NM_000546.6:c.574C>T as the nonsense variant NP_000537.3:p.(Gln192Ter), also p.(Q192*).
Still missing
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in PP3-BP4-codes.xlsx.txt.
  • No entry for c.574C>T, p.Gln192Ter, or p.Q192* was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1

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. BayesDel score = 0.66.

9 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 paper does not mention TP53 c.574C>T or NP_000537.3:p.(Q192*). It investigated 184 missense mutant p53 proteins in the C-terminal tetramerization/oligomerization domain (residues 322-354), using yeast-based oligomer-formation and transcriptional-activation assays; because p.(Q192*) is a truncating variant outside the domain examined, it provides no direct functional result for this variant.
    Does not name this variant
    PMID 16007150 ↗
    Quoted passage
    Among 193 mutant p53s constructed in 33 residues from 322 to 354, we chose to examine 184 (95.3%) mutant p53s.

    Results, paragraph describing the analyzed mutant library; Table 1

  • High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.
    This paper does not report TP53 c.574C>T or p.(Q192*). It describes TP53 protein-truncating mutations generally in breast tumors, including nonsense, frameshift, and splice mutations, but provides no variant-specific functional assay result for p.Q192*.
    Does not name this variant
    PMID 19336573 ↗
    Quoted passage
    we found a significantly larger proportion of protein-truncating frameshift, nonsense, and splice mutations in the BRCA1 tumor group (21.6%, 11 of 51) compared with the sporadic tumor group (3.0%, 2 of 67; P = 0.0061; Table 3A).

    Results, “Frequencies of TP53 mutation types”; Table 3A

  • Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.
    This paper does not explicitly mention TP53 c.574C>T or p.(Q192*). In a cohort of 141 head and neck squamous cell carcinomas, it identified truncating TP53 mutations and described them as producing nonfunctional protein, but did not provide an exact-variant assay result for p.Q192*.
    Does not name this variant
    PMID 21467160 ↗
    Quoted passage
    Truncating mutations lead to nonfunctional protein and are caused by nonsense mutations (resulting in stop codons), splice-site mutations, and frameshift deletions and insertions.

    Discussion, first paragraph; Results, “Truncating and missense TP53 mutations”

  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    No paper-specific finding is recorded.
    PMID 17392385 ↗
  • American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
    No paper-specific finding is recorded.
    PMID 23619274 ↗

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 6 Pathogenic · 1 Likely pathogenic 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 has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 406579)

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. BayesDel score = 0.66.

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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52660737, n = 267 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.