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TP53c.527G>TUncertain significance
Print report
Variant interpretation report

TP53 c.527G>T, p.(Cys176Phe)

NM_000546.6:c.527G>T NP_000537.3:p.(Cys176Phe) Missense · exon 5 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Moderate
PS3 · moderate

Met at moderate: the VCEP worksheet assigns C176F PS3_Moderate, with partially functional Kato results and loss of function in three other eligible assays.

PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v4.1 AF is 1.23897e-06, below the TP53 VCEP PM2 threshold of 0.00003.

PP3Moderate
PP3 · moderate

Met: the TP53 VCEP lookup pre-assigns PP3_moderate for c.527G>T / p.Cys176Phe with BayesDel score 0.579613 and C65 classification.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PS3 moderate, PM2 supporting, and PP3 moderate total 5 points under the TP53 Expert Panel's Version 2.4 point-based framework.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,614,238 alleles

gnomAD v4.1: 2 / 1,614,238 alleles. Recorded AF 1.23897e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97956e-06; MAF= 0.00040%, 1/251284 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80297e-06; MAF= 0.00088%, 1/113598 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.951 recorded score

Recorded REVEL score: 0.951. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 →
ClinVar submissions
4 reported laboratory submissions

2 Likely pathogenic · 1 Likely Pathogenic · 1 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: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
343 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52661329, n = 343 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: 3 met · 4 not met · 9 not assessed · 12 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 governing TP53 VCEP functional worksheet directly assigns PS3_Moderate to C176F based on partially functional Kato data and LOF in the Funk, Giacomelli, and Kotler assays.

The same assignment and assay pattern rule out BS3; no benign functional code is assigned.

The TP53 VCEP governs this group. PS4 and PP4 cannot be assessed because the available exact-variant cancer observations do not provide the required germline PS4 point tally or PP4 VAF evidence; PP5, BP5, and BP6 are explicitly not applicable under the VCEP.

The exact variant was searched as c.527G>T, p.Cys176Phe, and p.C176F in the supplied TP53 full-text VCEP files; no variant-specific table entry was found.

For this missense variant, the TP53 VCEP exact-variant lookup governs PP3 and pre-assigns PP3_moderate.

BP4 is not met because the missense-path BayesDel score 0.579613 is above the TP53 VCEP benign threshold; the low SpliceAI score is not transferable to missense BP4.

BP7 is not applicable because the variant is missense rather than synonymous or intronic.

Met · 3

PS3 ModerateMet at moderate: the VCEP worksheet assigns C176F PS3_Moderate, with partially functional Kato results and loss of function in three other eligible assays. Details ▾Hide ▴
Reasoning

The TP53 VCEP Functional-worksheet.xlsx assigns C176F (the protein consequence of NM_000546.6:c.527G>T) PS3_Moderate. The governing row records Kato as partially functional and Funk, Giacomelli, and Kotler as loss of function, with Kawaguchi not available. This satisfies the TP53 VCEP rule for PS3_Moderate: partially functional on Kato et al. data and loss of function by the majority of other available eligible assays. The functional flowchart identifies these assays as eligible and provides no contrary variant-specific assignment. Independent literature also directly reports C176F as a disruptive TP53 mutation in cellular models, with radioresistance and absent radiation-induced p21 induction, supporting loss of tumor-suppressor function but not changing the VCEP-assigned strength.

Rule
PS3_Moderate: Partially functional on Kato et al. data AND loss of function (LOF) by the majority of other available assays.
Evidence considered
  • The TP53 VCEP Functional-worksheet.xlsx row for C176F records Kato: Partially functional; Funk: LOF; Giacomelli: LOF; Kotler: LOF; Kawaguchi: NA; preliminary functional code: PS3_Moderate.
  • The TP53 VCEP specification defines PS3_Moderate as partially functional on Kato et al. data plus loss of function by the majority of other available assays.
  • The TP53 VCEP functional flowchart lists Kato, Funk, Giacomelli, Kotler, and Kawaguchi as eligible functional studies for PS3/BS3 assessment.
  • PMID:22090360 directly studied C176F in HNSCC cellular models and reported it as disruptive; C176F-expressing cells were radioresistant relative to wild type and nondisruptive TP53 controls and showed no radiation-induced p21 induction.
Still missing
  • The functional flowchart file was searched for c.527G>T, p.Cys176Phe, and p.C176F; it contains no variant-specific entry, but it is a general application flowchart rather than the assignment table.
  • Kawaguchi assay data are listed as NA for C176F in the governing worksheet.
Sources
vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetcspec ↗PMID:22090360 ↗
PM2 SupportingMet at supporting: gnomAD v4.1 AF is 1.23897e-06, below the TP53 VCEP PM2 threshold of 0.00003. Details ▾Hide ▴
Reasoning

The TP53 VCEP v2.4 PM2 rule is applied at supporting strength when the allele frequency is below 0.00003 in gnomAD or another large sequenced population; if multiple alleles are present within an ancestry group, that group must remain below 0.00004. The default all-comers gnomAD v4.1 data show AF 1.23897e-06 (2/1,614,238 alleles), grpmax FAF 2.8e-07, and 0 homozygotes. The VCEP-relevant non-cancer exome data are also below threshold: gnomAD v2.1 non-cancer exomes AF 4.22358e-06 (1/236,766), and the highest non-cancer ancestry AF is 4.05976e-05 from one allele in NFE_ONF, so the multiple-allele ancestry condition is not triggered. The variant therefore meets PM2 Supporting.

Rule
TP53 VCEP v2.4 PM2: supporting when AF <0.00003; if multiple alleles are present within an ancestry group, that group's AF must be <0.00004; ignore founder-effect groups.
Evidence considered
  • TP53 VCEP v2.4 specifies PM2 Supporting for AF <0.00003 in gnomAD or another large sequenced population; when multiple alleles occur in an ancestry group, that group must have AF <0.00004, with founder-effect groups ignored.
  • gnomAD v4.1 all-comers reports AF 1.23897e-06 from 2/1,614,238 alleles, grpmax FAF 2.8e-07, and 0 homozygotes.
  • gnomAD v2.1 non-cancer exomes report AF 4.22358e-06 from 1/236,766 alleles and 0 homozygotes; the highest listed non-cancer ancestry AF is 4.05976e-05 from 1/24,632 NFE_ONF alleles, so the VCEP multiple-allele ancestry clause does not apply.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
PP3 ModerateMet: the TP53 VCEP lookup pre-assigns PP3_moderate for c.527G>T / p.Cys176Phe with BayesDel score 0.579613 and C65 classification. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the TP53 VCEP missense computational rule applies. The governing PP3-BP4-codes.xlsx lookup contains the exact row c.527G>T / p.Cys176Phe with BayesDel class C65, BayesDel score 0.579613, and a pre-assigned PP3_moderate code. This VCEP pre-assignment governs and is applied directly; SpliceAI is not used to support missense PP3/BP4. The searched single-amino-acid-deletions spreadsheet has no entry for this missense variant and is not applicable.

Rule
TP53 VCEP PP3_moderate pre-assignment for the exact missense row in PP3-BP4-codes.xlsx.
Evidence considered
  • The TP53 VCEP PP3-BP4 lookup table was searched for c.527G>T, p.Cys176Phe, and p.C176F; the exact c.527G>T row assigns Class C65, BayesDel 0.579613, and PP3_moderate.
  • The TP53 VCEP specification defines PP3_moderate for missense variants with aGVGD C65 and BayesDel score at least 0.16; the exact lookup-table pre-assignment takes precedence over independently recomputing the code.
  • Case normalization identifies NM_000546.6:c.527G>T as the missense variant NP_000537.3:p.(Cys176Phe) / p.(C176F).
Still missing
  • No c.527G>T, p.Cys176Phe, or p.C176F entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx; that deletion-specific table is not applicable to this missense variant.
Sources
cspec ↗vcep_pp3_bp4_codesbayesdel

Not met · 4 · evaluated, threshold not reached

BA1 Not met: gnomAD v4.1 maximum population FAF is 2.8e-07, below the TP53 VCEP BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The TP53 VCEP v2.4 BA1 rule requires a filtering allele frequency (FAF) of at least 0.001 in a qualifying continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles. gnomAD v4.1 reports a maximum population FAF of 2.8e-07 and the highest observed ancestry frequency is 1.69485e-06 (2/1,180,046 in European non-Finnish individuals), far below 0.001. The gnomAD v2.1 non-cancer exome frequency is also only 4.22358e-06, so the stand-alone benign threshold is not reached.

Rule
TP53 VCEP v2.4 BA1: FAF >=0.001 in a qualifying continental subpopulation, with >=2,000 alleles tested and >=2 variant alleles; exclude founder-effect groups.
Evidence considered
  • TP53 VCEP v2.4 specifies BA1 at FAF >=0.001 in a qualifying continental ancestry group, excluding founder-effect groups, with at least 2,000 alleles tested and at least 2 variant alleles.
  • gnomAD v4.1 reports grpmax FAF 2.8e-07; its highest observed ancestry frequency is 1.69485e-06 from 2/1,180,046 European non-Finnish alleles, with 0 homozygotes.
  • gnomAD v2.1 non-cancer exomes report AF 4.22358e-06 from 1/236,766 alleles, with 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS1 Not met: gnomAD v4.1 maximum population FAF is 2.8e-07, below the TP53 VCEP BS1 lower threshold of 0.0003. Details ▾Hide ▴
Reasoning

The TP53 VCEP v2.4 BS1 rule requires a filtering allele frequency of 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. gnomAD v4.1 reports grpmax FAF 2.8e-07 and a highest ancestry frequency of 1.69485e-06, both below 0.0003. The gnomAD v2.1 non-cancer exome subgroup with the highest reported frequency has only one observed allele and a frequency of 4.05976e-05 in NFE_ONF, which does not meet the VCEP minimum two-allele requirement; the broader v2.1 non-cancer NFE frequency is 9.74735e-06.

Rule
TP53 VCEP v2.4 BS1: 0.0003 <= FAF < 0.001 in a qualifying continental subpopulation, with >=2,000 alleles tested and >=2 variant alleles; exclude founder-effect groups.
Evidence considered
  • TP53 VCEP v2.4 specifies BS1 at FAF >=0.0003 and <0.001 in a qualifying continental subpopulation, excluding founder-effect groups, with at least 2,000 alleles tested and at least 2 variant alleles.
  • gnomAD v4.1 reports grpmax FAF 2.8e-07 and the highest ancestry AF is 1.69485e-06 from 2/1,180,046 European non-Finnish alleles.
  • In gnomAD v2.1 non-cancer exomes, the NFE_ONF subgroup is 1/24,632 alleles (AF 4.05976e-05), so it fails the VCEP requirement for at least 2 variant alleles; the aggregate non-cancer exome AF is 4.22358e-06.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS3 Not met: the VCEP worksheet assigns PS3_Moderate and records loss of function in three eligible assays, precluding a benign functional interpretation. Details ▾Hide ▴
Reasoning

BS3 is not supported under the TP53 VCEP specification. The governing Functional-worksheet.xlsx assigns C176F PS3_Moderate, not BS3, and records loss of function in the Funk, Giacomelli, and Kotler assays. The TP53 VCEP BS3 rules require functional or partially functional Kato results together with no loss of function by the required set of available eligible assays; the observed majority LOF pattern is incompatible with that benign functional criterion.

Rule
BS3 is applicable only when TP53 VCEP functional results are functional on Kato and show no loss of function by the majority of available eligible assays; BS3_Supporting requires partially functional Kato data and no LOF by all available assays.
Evidence considered
  • The TP53 VCEP Functional-worksheet.xlsx row for C176F assigns PS3_Moderate and records LOF for Funk, Giacomelli, and Kotler, with Kawaguchi NA.
  • The TP53 VCEP BS3 rule requires functional Kato data and no loss of function by the majority of available eligible assays; the C176F assay pattern does not satisfy this requirement.
Still missing
  • The functional flowchart file was searched for c.527G>T, p.Cys176Phe, and p.C176F; it contains no variant-specific entry, but it is a general application flowchart rather than the assignment table.
  • Kawaguchi assay data are listed as NA for C176F in the governing worksheet.
Sources
vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetcspec ↗
BP4 Not met: missense BayesDel 0.579613 exceeds the TP53 VCEP BP4 threshold of <0.16, so the SpliceAI max delta 0.004 cannot establish BP4. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so BP4 must be assessed on the missense computational path and cannot be supported by its low SpliceAI score. The governing TP53 VCEP specification requires BayesDel below 0.16 for missense BP4_supporting, or at most -0.008 for BP4_moderate, together with no predicted splice difference. The case BayesDel score is 0.579613, which exceeds the VCEP benign thresholds, so BP4 is not met despite SpliceAI max delta 0.004. The exact VCEP lookup row assigns PP3_moderate and does not assign BP4. The searched single-amino-acid-deletions spreadsheet has no entry for this missense variant and is not applicable.

Rule
TP53 VCEP missense BP4 requires BayesDel <0.16 for supporting or <=-0.008 for moderate, plus no predicted splice difference.
Evidence considered
  • The TP53 VCEP specification sets missense BP4_supporting at BayesDel <0.16 and BP4_moderate at BayesDel <=-0.008, with no predicted splicing difference.
  • The case BayesDel score is 0.579613, above both TP53 VCEP benign thresholds; therefore BP4 is not met.
  • The case SpliceAI maximum delta is 0.004, but SpliceAI cannot substitute for the missense REVEL/BayesDel path or provide BP4 support for the amino-acid substitution.
  • The exact TP53 VCEP lookup row c.527G>T / p.Cys176Phe assigns PP3_moderate and does not assign BP4.
Still missing
  • No c.527G>T, p.Cys176Phe, or p.C176F entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx; that deletion-specific table is not applicable to this missense variant.
Sources
cspec ↗vcep_pp3_bp4_codesbayesdelspliceai ↗

Not assessed · 9 · no assessment recorded

PS1 Not assessed: no qualifying independent variant with a different nucleotide change producing the same p.Cys176Phe amino-acid substitution was identified. Details ▾Hide ▴
Reasoning

The variant is TP53 NM_000546.6:c.527G>T, p.Cys176Phe. PS1 requires an independently established pathogenic variant producing the same amino-acid change through a different nucleotide change. The reviewed evidence identifies Cys176Phe itself, but does not identify a different nucleotide change yielding p.Cys176Phe or provide a qualifying VCEP-reviewed PS1 assertion. The TP53 VCEP permits PS1 only for variants asserted as pathogenic or likely pathogenic under its specifications, and the available ClinVar submissions are not Expert Panel submissions; therefore the prerequisite evidence for PS1 cannot be verified.

Rule
Can be applied to variants asserted as Pathogenic or Likely Pathogenic following the TP53 VCEP specifications.
Evidence considered
  • The TP53 VCEP PS1 rule allows PS1 for variants asserted pathogenic or likely pathogenic following TP53 VCEP specifications, with strong and moderate strengths respectively.
  • ClinVar records the queried c.527G>T (p.Cys176Phe) variant as pathogenic/likely pathogenic without an Expert Panel submission, but this is evidence about the queried variant itself and does not establish PS1 from a distinct nucleotide change.
  • No paper extract reviewed for this group documents a second nucleotide change producing p.Cys176Phe.
Still missing
  • A qualifying alternate nucleotide change producing p.Cys176Phe with an established VCEP-concordant pathogenic or likely pathogenic classification is not documented.
Sources
cspec ↗clinvar ↗
PS2 Not assessed: no confirmed de novo proband, parental testing, or TP53 VCEP PS2 point assignment is documented for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP version 2.4 specifies that de novo evidence is assessed exclusively with PS2, that PM6 is not used, and that PS2 strength is based on the total points assigned to confirmed de novo probands: 1 point for Supporting, 2-3 for Moderate, 4-7 for Strong, and at least 8 for Very Strong. The available case evidence contains no documented proband, confirmed maternity and paternity, parental testing results, constitutional mosaicism, phenotype-specific de novo point assignment, or other confirmed de novo observation for NM_000546.6:c.527G>T (p.Cys176Phe/p.C176F), so PS2 cannot be assigned.

Rule
TP53 VCEP PS2: tally de novo points for confirmed de novo probands; Supporting = 1 point, Moderate = 2-3 points, Strong = 4-7 points, Very Strong = at least 8 points. PM6 is not used by this VCEP.
Evidence considered
  • The TP53 VCEP version 2.4 PS2 rule states that the VCEP dropped PM6 and uses PS2 exclusively for de novo evidence.
  • The TP53 VCEP version 2.4 PS2 thresholds are Supporting for 1 point, Moderate for 2-3 points, Strong for 4-7 points, and Very Strong for at least 8 points.
  • The case evidence documents the variant and functional/literature observations but does not document a confirmed de novo proband, parental testing, or de novo point-bearing clinical observation.
Still missing
  • No confirmed de novo proband, maternity and paternity confirmation, parental genotypes, or constitutional mosaicism data are available for this case.
  • No variant-specific entry was found when searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt for c.527G>T, p.Cys176Phe, or p.C176F; this table is a generic cancer-point and threshold table rather than a variant case series.
Sources
cspec ↗
PS4 Not assessed: the exact-variant tumor reports lack germline status and the VCEP-defined PS4 cancer-point total needed to reach the >=1-point threshold. Details ▾Hide ▴
Reasoning

The TP53 VCEP governs PS4 by proband points: Supporting requires 1-1.5 points, Moderate 2-3.5, Strong 4-7.5, and Very Strong >=8 points. The searched PS4-Points-Table.pdf contains no extracted variant-specific entry for c.527G>T, p.Cys176Phe, or p.C176F. PMID:15611505 reports Cys176Phe in three ethmoid adenocarcinoma tumor specimens, but supplies neither germline status nor the VCEP-defined LFS proband cancer-point data needed to assign PS4. Therefore PS4 cannot be assessed from the available evidence; the tumor observations must not be converted into germline phenotype prevalence evidence.

Rule
PS4: >=8 points Very Strong; >=4-7.5 points Strong; 2-3.5 points Moderate; 1-1.5 points Supporting.
Evidence considered
  • The TP53 VCEP PS4 rules assign Supporting at 1-1.5 points, Moderate at 2-3.5 points, Strong at 4-7.5 points, and Very Strong at >=8 points.
  • The full-text search of PS4-Points-Table.pdf found no entry for c.527G>T, p.Cys176Phe, or p.C176F.
  • PMID:15611505 reports Cys176Phe/TGC>TTC in three patients with ethmoid intestinal-type adenocarcinoma; the study sequenced pretreatment tumor biopsies and does not establish germline status or provide the TP53 VCEP LFS cancer-point tally.
Still missing
  • No exact-variant entry was found when searching PS4-Points-Table.pdf for c.527G>T, p.Cys176Phe, and p.C176F.
  • No validated germline proband phenotype data or VCEP PS4 cancer-point tally is available for this case.
Sources
cspec ↗vcep_ps4_points_tablePMID:15611505 ↗
PM1 Not assessed: p.Cys176Phe is outside the VCEP codon list, while the partial C176 hotspot record lacks the required same-amino-acid count of at least 10. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP specifies PM1 at Moderate strength for missense variants in codons 175, 245, 248, 249, 273, or 282, or for a germline missense variant seen in cancerhotspots.org v2 with at least 10 somatic occurrences for the same amino-acid change. p.Cys176Phe is at codon 176, so it does not meet the listed codon rule. The case evidence reports a statistically significant C176 hotspot, and published evidence places Cys176 in the TP53 zinc-binding site, but the hotspot extraction is partial and does not document the required same-amino-acid occurrence count; the PM1 rule therefore cannot be verified from the available record.

Rule
Missense variants within codons 175, 245, 248, 249, 273, or 282, or germline missense variants seen in cancerhotspots.org v2 with at least 10 somatic occurrences for the same amino-acid change.
Evidence considered
  • The TP53 VCEP PM1 Moderate rule lists codons 175, 245, 248, 249, 273, and 282, and alternatively requires at least 10 cancerhotspots.org v2 somatic occurrences for the same amino-acid change.
  • The variant is p.Cys176Phe, codon 176, which is not one of the VCEP's explicitly listed codons.
  • The case hotspot result says C176 lies in a statistically significant hotspot but warns that extraction was partial and supplies no qualifying same-amino-acid occurrence count.
  • PMID:10713666 describes Cys176 as part of the TP53 zinc-binding site and a minor cancer-associated hotspot; PMID:15037740 identifies C176F as a zinc-binding-site mutation. These publications provide biological context but do not replace the VCEP's required hotspot threshold.
Still missing
  • The cancerhotspots.org v2 record must document at least 10 somatic occurrences for the same p.Cys176Phe amino-acid change before VCEP PM1 can be applied.
Sources
cspec ↗PMID:10713666 ↗PMID:15037740 ↗
PM5 Not assessed: no qualifying different missense substitution at Cys176 with a VCEP-concordant pathogenic or clinically supported likely pathogenic classification was identified. Details ▾Hide ▴
Reasoning

The TP53 VCEP PM5 rule requires a different missense substitution at the same amino-acid residue that has been determined pathogenic under the TP53 VCEP specifications, with Moderate strength for one pathogenic comparator, Strong for at least two pathogenic comparators, or Supporting for one clinically supported likely pathogenic comparator. The same-residue comparator search returned no useful candidates, and the reviewed paper extracts do not establish a qualifying pathogenic or likely pathogenic comparator at Cys176. Functional or general zinc-binding-site observations alone cannot establish PM5.

Rule
One different missense variant at the same residue previously determined pathogenic, or one clinically supported likely pathogenic variant at the same residue, according to TP53 VCEP specifications.
Evidence considered
  • The TP53 VCEP requires one different pathogenic missense variant at the same residue for PM5_Moderate, at least two for PM5_Strong, or one clinically supported likely pathogenic comparator for PM5_Supporting.
  • The dedicated same-residue comparator artifact reports zero same-residue candidates and no useful candidates; it also reports a soft retrieval failure.
  • PMID:10713666 discusses zinc-region TP53 substitutions but experimentally evaluates other variants rather than providing a qualifying pathogenic Cys176 comparator.
  • PMID:15037740 names C176F among zinc-binding-site mutations but does not establish a different Cys176 missense variant as a VCEP-qualified pathogenic comparator.
Still missing
  • A distinct Cys176 missense comparator and its qualifying VCEP-concordant pathogenicity evidence are needed.
Sources
cspec ↗PMID:10713666 ↗PMID:15037740 ↗
PP1 Not assessed: no affected relatives, family genotypes, or counted cosegregating meioses are documented for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP version 2.4 requires cosegregation across 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. No affected relatives, unaffected relatives, parental genotypes, family structure, phase information, or counted cosegregating meioses are documented for NM_000546.6:c.527G>T (p.Cys176Phe/p.C176F), so PP1 cannot be assigned.

Rule
TP53 VCEP PP1: Supporting = 3-4 cosegregating meioses; Moderate = 5-6 meioses; Strong = at least 7 meioses across more than one family.
Evidence considered
  • The TP53 VCEP version 2.4 PP1 rules require 3-4 cosegregating meioses for Supporting, 5-6 for Moderate, and at least 7 meioses across more than one family for Strong.
  • The case evidence does not document a family pedigree, affected-relative testing, unaffected-relative testing, phase, or any meiosis count for this variant.
Still missing
  • No family pedigree, affected or unaffected relative genotypes, phase information, or meiosis count is available for PP1 assessment.
  • No variant-specific entry was found when searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt for c.527G>T, p.Cys176Phe, or p.C176F; this table is a generic cancer-point and threshold table rather than a variant case series.
Sources
cspec ↗
PP4 Not assessed: no qualifying multigene-panel VAF observation between 5% and 35% is documented for this TP53 variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP PP4 specification is applicable only to a TP53 variant observed at low VAF in multigene panel testing, with Supporting evidence for an observation at VAF 5-35% and Moderate evidence for at least two independent observations at VAF 5-25%; it also requires the somatic-origin caveats to be satisfied. The available case evidence provides no qualifying VAF observation, multigene-panel context, or exclusion of blood cancer, confirmed constitutional mosaicism, or another relevant caveat. PP4 therefore cannot be assessed.

Rule
PP4: Supporting for an observation at VAF 5-35%; Moderate for at least 2 independent observations at VAF 5-25%, subject to the TP53 VCEP caveats.
Evidence considered
  • The TP53 VCEP PP4 Supporting rule requires observation at VAF 5-35%; the Moderate rule requires at least two independent observations at VAF 5-25%.
  • The specification requires multigene-panel detection and states that PP4 cannot be combined with phenotype-based codes in the same individual and should not be used for blood cancer or when BA1/BS1 applies.
  • No qualifying VAF, multigene-panel context, or complete PP4 caveat assessment is present in the case evidence.
Still missing
  • No qualifying VAF and multigene-panel observation is documented for PP4.
  • The required PP4 somatic-origin caveats cannot be evaluated from the available case evidence.
Sources
cspec ↗
BS2 Not assessed: no qualifying count of unrelated female carriers aged at least 60 years without cancer is available. Details ▾Hide ▴
Reasoning

The TP53 VCEP v2.4 BS2 rule requires observations in unrelated females aged at least 60 years without cancer, all from one source: supporting for 2-3, moderate for 4-7, or strong for at least 8 individuals. The available case evidence contains no qualifying unaffected older-female carrier observations or source-level carrier count.

Rule
TP53 VCEP v2.4 BS2: unrelated females aged >=60 years without cancer from one source; 2-3 supporting, 4-7 moderate, >=8 strong.
Evidence considered
  • TP53 VCEP v2.4 defines BS2 as 2-3 qualifying unrelated females aged at least 60 years without cancer for supporting, 4-7 for moderate, or at least 8 for strong, all from one source; individuals with sarcoma at age 61 or older are excluded.
  • No qualifying unaffected older-female carrier observations are reported in the available evidence.
Still missing
  • A single-source cohort or database count of unrelated female carriers aged >=60 years without cancer is needed.
Sources
cspec ↗
BS4 Not assessed: no affected relatives with discrepant genotypes or documented non-segregation are available for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP version 2.4 defines BS4 as strong evidence for lack of segregation in affected family members with LFS-associated cancers, while cautioning that phenocopies and more than one pathogenic variant can confound apparent non-segregation. No affected family members, family genotypes, non-segregation observations, phenocopy assessment, or alternate familial pathogenic-variant assessment are documented for NM_000546.6:c.527G>T (p.Cys176Phe/p.C176F), so BS4 cannot be assigned.

Rule
TP53 VCEP BS4: Strong for lack of segregation in affected family members with LFS-associated cancers, considering phenocopies and additional familial pathogenic variants as confounders.
Evidence considered
  • The TP53 VCEP version 2.4 BS4 rule applies at Strong strength for lack of segregation in affected family members with LFS-associated cancers.
  • The TP53 VCEP cautions that phenocopies and more than one pathogenic variant in a family can mimic or confound lack of segregation.
  • The case evidence contains no family segregation or non-segregation observations for this variant.
Still missing
  • No family pedigree or genotype/phenotype data are available to establish lack of segregation in affected relatives.
  • No assessment is available for phenocopies or additional pathogenic variants that could confound apparent non-segregation.
Sources
cspec ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.527G>T is a missense variant yielding p.Cys176Phe, not a TP53 VCEP-defined null or canonical splice variant eligible for PVS1. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. NM_000546.6:c.527G>T produces the missense substitution NP_000537.3:p.(Cys176Phe) (p.C176F), not a nonsense, frameshift, canonical ±1,2 splice, initiation-codon, or copy-number null variant. The TP53 VCEP PVS1 flowchart governs null variants on NM_000546.6, and the PVS1 splicing worksheet contains no entry for c.527G>T, p.Cys176Phe, or p.C176F; therefore no PVS1 strength tier applies. The generic PVS1 framework is not used because the gene-specific TP53 VCEP framework is applicable and this missense consequence is outside its PVS1 scope.

Rule
TP53 VCEP PVS1 decision tree: applicable only to specified null and canonical splice consequences; missense c.527G>T is outside scope.
Evidence considered
  • The case normalization identifies NM_000546.6:c.527G>T as NP_000537.3:p.(Cys176Phe), also p.C176F, with consequence class missense and canonical_splice_consensus false.
  • The TP53 VCEP PVS1 flowchart applies to null variants including nonsense, frameshift, canonical splice-site, initiation-codon, and copy-number variants; it does not assign PVS1 to this missense substitution.
  • The complete TP53 PVS1 splicing worksheet was searched for c.527G>T, p.Cys176Phe, and p.C176F; no matching row was found.
Still missing
  • No entry for c.527G>T, p.Cys176Phe, or p.C176F was found in PVS1-Flowchart.pdf.txt.
  • No entry for c.527G>T, p.Cys176Phe, or p.C176F was found in PVS1-Splicing-Worksheet.xlsx.txt.
Sources
cspec ↗vcep_pvs1_flowchartvcep_pvs1_splicing_worksheet
PM3 VCEPNot applicable: the TP53 VCEP explicitly excludes PM3 for Li-Fraumeni syndrome, regardless of phase or affected-proband observations. Details ▾Hide ▴
Reasoning

PM3 is not applicable under the ClinGen TP53 Expert Panel Specifications, version 2.4. The TP53-specific rule explicitly states that PM3 does not apply to TP53/Li-Fraumeni syndrome; therefore, phase, affected-proband observations, and trans configuration cannot activate PM3 for this case.

VCEP rule
This rule does not apply to TP53/Li-Fraumeni syndrome.
Evidence considered
  • The TP53 VCEP version 2.4 marks PM3 as not applicable and states: This rule does not apply to TP53/Li-Fraumeni syndrome.
  • Because PM3 is excluded by the governing gene-specific framework, no generic recessive-disease trans-phase rule was applied.
Sources
cspec ↗
PM4 VCEPNot applicable: the TP53 VCEP explicitly designates PM4 as Not Applicable, and c.527G>T is a missense substitution rather than a protein-length-altering indel. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the TP53 VCEP specifications, which explicitly designate PM4 as Not Applicable. This variant is a missense substitution, p.Cys176Phe, rather than a protein-length-altering in-frame deletion, insertion, or indel for which PM4 could otherwise be considered under generic ACMG/AMP guidance.

VCEP rule
TP53 VCEP v2.4: PM4 is Not Applicable.
Evidence considered
  • The TP53 VCEP ACMG/AMP specifications v2.4 explicitly list PM4 as Not Applicable.
  • NM_000546.6:c.527G>T is normalized as the missense change NP_000537.3:p.(Cys176Phe), not an in-frame deletion, insertion, or other protein-length-altering variant.
Sources
cspec ↗
PM6 VCEPNot applicable: the TP53 VCEP explicitly drops PM6 and uses PS2 exclusively for de novo evidence. Details ▾Hide ▴
Reasoning

The TP53 VCEP version 2.4 explicitly states that PM6 is dropped and PS2 is used exclusively for de novo evidence; therefore PM6 is not applicable under the governing gene-specific framework.

VCEP rule
TP53 VCEP PM6: not applicable; see the combined PS2/PM6 rule, with PS2 used exclusively for de novo evidence.
Evidence considered
  • The TP53 VCEP version 2.4 PS2 instructions state that, to avoid redundancy and increase consistency, PM6 is dropped and PS2 is used exclusively for de novo TP53 evidence.
Sources
cspec ↗
PP2 VCEPNot applicable: the TP53 VCEP explicitly excludes PP2 for this gene. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP explicitly marks PP2 as not applicable. No generic PP2 assessment is used because an applicable gene-specific specification takes precedence.

VCEP rule
Not applicable for TP53.
Evidence considered
  • The TP53 VCEP criterion definition marks PP2 as not applicable and provides no applicable strength rule.
Sources
cspec ↗
PP5 VCEPNot applicable: the TP53 VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification. 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. Independently, the exact-variant ClinVar record has no expert-panel submission; it contains only single-submitter laboratory assertions. Thus the required exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification is absent and PP5 is not applicable.

VCEP rule
PP5 is not applicable under the TP53 VCEP; an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification would otherwise be required by the requested framework.
Evidence considered
  • The TP53 VCEP specification states that PP5 is not applicable and is not for use.
  • The exact-variant ClinVar record is classified through single-submitter laboratory assertions and records zero expert-panel submissions; ordinary laboratory and aggregate labels do not trigger PP5.
Sources
cspec ↗clinvar ↗
BP1 VCEPNot applicable: the TP53 VCEP excludes BP1 because truncating variants are not the primary disease mechanism. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP explicitly marks BP1 as not applicable because truncating variants account for only a portion of disease-causing TP53 variants. No generic BP1 assessment is used because an applicable gene-specific specification takes precedence.

VCEP rule
This rule code does not apply to TP53 because truncating variants account for only a portion of disease-causing variants.
Evidence considered
  • The TP53 VCEP BP1 instruction states that BP1 does not apply because truncating variants account for only a portion of disease-causing variants in TP53.
Sources
cspec ↗
BP2 VCEPNot applicable: the TP53 VCEP marks BP2 not applicable and provides no usable strength rule for trans/cis or phase evidence. Details ▾Hide ▴
Reasoning

BP2 is not applicable under the ClinGen TP53 Expert Panel Specifications, version 2.4. Although the generic BP2 concept concerns a pathogenic or likely pathogenic TP53 variant observed in trans with confirmed phase or repeated observations with unknown phase, the governing TP53 VCEP marks BP2 not applicable and supplies no applicable strength rule; generic BP2 therefore cannot be used.

VCEP rule
Evidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic or likely pathogenic TP53 variants.
Evidence considered
  • The TP53 VCEP version 2.4 marks BP2 as not applicable and provides no applicable strength rule.
  • The VCEP instructions describe generic trans-phase scenarios, but the criterion's governing applicability is not applicable; those scenarios therefore do not permit BP2 in TP53/Li-Fraumeni syndrome.
Sources
cspec ↗
BP3 VCEPNot applicable: the TP53 VCEP explicitly designates BP3 as Not Applicable, and c.527G>T is a missense substitution rather than a repeat-region in-frame indel. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the TP53 VCEP specifications, which explicitly designate BP3 as Not Applicable. This variant is a missense substitution, p.Cys176Phe, not an in-frame deletion or insertion in a repetitive region with no predicted functional impact.

VCEP rule
TP53 VCEP v2.4: BP3 is Not Applicable.
Evidence considered
  • The TP53 VCEP ACMG/AMP specifications v2.4 explicitly list BP3 as Not Applicable.
  • NM_000546.6:c.527G>T is normalized as the missense change NP_000537.3:p.(Cys176Phe), not an in-frame insertion or deletion in a repetitive region.
Sources
cspec ↗
BP5 VCEPNot applicable: the TP53 VCEP excludes BP5, and no alternate molecular basis is documented for this case. Details ▾Hide ▴
Reasoning

The TP53 VCEP explicitly marks BP5 as not applicable and provides no usable TP53-specific BP5 rule. No alternate molecular basis for the disease is documented in the available case evidence. Because the governing VCEP specification excludes BP5, it is not applicable rather than met or not_met.

VCEP rule
BP5 is not applicable under the TP53 VCEP.
Evidence considered
  • The TP53 VCEP specification marks BP5 as not applicable and supplies no applicable strength rule.
  • No alternate molecular diagnosis is documented in the evidence reviewed.
Sources
cspec ↗
BP6 VCEPNot applicable: the TP53 VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification. 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. Independently, the exact-variant ClinVar record has no expert-panel submission and no expert-panel Benign/Likely benign classification; the available assertions are single-submitter laboratory classifications in the pathogenic direction. Therefore BP6 is not applicable.

VCEP rule
BP6 is not applicable under the TP53 VCEP; an exact-variant ClinVar expert-panel Benign/Likely benign classification would otherwise be required by the requested framework.
Evidence considered
  • The TP53 VCEP specification states that BP6 is not applicable and is not for use.
  • The exact-variant ClinVar record has zero expert-panel submissions and only single-submitter laboratory assertions; no exact-variant expert-panel Benign/Likely benign classification is present.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: c.527G>T is a missense variant producing p.Cys176Phe, whereas BP7 is restricted to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_000546.6:c.527G>T produces the missense substitution p.Cys176Phe (p.C176F), so BP7 is outside its criterion scope and is not evaluated.

Rule
TP53 VCEP BP7 scope: synonymous or qualifying intronic variants only.
Evidence considered
  • The TP53 VCEP BP7 rule applies to synonymous or intronic variants, not missense substitutions.
  • Case normalization identifies c.527G>T as the missense substitution p.Cys176Phe / p.C176F.
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.527G>T
Protein (HGVS p.)
NP_000537.3:p.(Cys176Phe)
GRCh38
chr17:7675085 C>A
GRCh37
chr17:7578403 C>A
Location and type
Exon 5 · missense
ClinVar
3328160, 376660, 376569
COSMIC
COSV52661329

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 2 / 1,614,238 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1 1 / 251,284 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,614,238 alleles · 0 hom · FAF 2.8e-07
European (non-Finnish)2 / 1,180,046 1.7e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,284 alleles · 0 hom
European (non-Finnish)1 / 113,598 8.8e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.23897e-06; MAF= 0.00012%, 2/1614238 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69485e-06; MAF= 0.00017%, 2/1180046 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97956e-06; MAF= 0.00040%, 1/251284 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80297e-06; MAF= 0.00088%, 1/113598 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +151 bp
0.000
SpliceAI acceptor gainat -114 bp
0.003
SpliceAI donor lossat -231 bp
0.003
SpliceAI donor gainat +14 bp
0.004
Pangolin splice lossmagnitude shown
-0.002
Pangolin splice gain
0.006

Other predictors

REVEL
0.951
BayesDel
0.580

How the predictions were used

PP3 ModerateMet: the TP53 VCEP lookup pre-assigns PP3_moderate for c.527G>T / p.Cys176Phe with BayesDel score 0.579613 and C65 classification. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the TP53 VCEP missense computational rule applies. The governing PP3-BP4-codes.xlsx lookup contains the exact row c.527G>T / p.Cys176Phe with BayesDel class C65, BayesDel score 0.579613, and a pre-assigned PP3_moderate code. This VCEP pre-assignment governs and is applied directly; SpliceAI is not used to support missense PP3/BP4. The searched single-amino-acid-deletions spreadsheet has no entry for this missense variant and is not applicable.

Rule
TP53 VCEP PP3_moderate pre-assignment for the exact missense row in PP3-BP4-codes.xlsx.
Evidence considered
  • The TP53 VCEP PP3-BP4 lookup table was searched for c.527G>T, p.Cys176Phe, and p.C176F; the exact c.527G>T row assigns Class C65, BayesDel 0.579613, and PP3_moderate.
  • The TP53 VCEP specification defines PP3_moderate for missense variants with aGVGD C65 and BayesDel score at least 0.16; the exact lookup-table pre-assignment takes precedence over independently recomputing the code.
  • Case normalization identifies NM_000546.6:c.527G>T as the missense variant NP_000537.3:p.(Cys176Phe) / p.(C176F).
Still missing
  • No c.527G>T, p.Cys176Phe, or p.C176F entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx; that deletion-specific table is not applicable to this missense variant.
Sources
cspec ↗vcep_pp3_bp4_codesbayesdel
BP4 Not met: missense BayesDel 0.579613 exceeds the TP53 VCEP BP4 threshold of <0.16, so the SpliceAI max delta 0.004 cannot establish BP4. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so BP4 must be assessed on the missense computational path and cannot be supported by its low SpliceAI score. The governing TP53 VCEP specification requires BayesDel below 0.16 for missense BP4_supporting, or at most -0.008 for BP4_moderate, together with no predicted splice difference. The case BayesDel score is 0.579613, which exceeds the VCEP benign thresholds, so BP4 is not met despite SpliceAI max delta 0.004. The exact VCEP lookup row assigns PP3_moderate and does not assign BP4. The searched single-amino-acid-deletions spreadsheet has no entry for this missense variant and is not applicable.

Rule
TP53 VCEP missense BP4 requires BayesDel <0.16 for supporting or <=-0.008 for moderate, plus no predicted splice difference.
Evidence considered
  • The TP53 VCEP specification sets missense BP4_supporting at BayesDel <0.16 and BP4_moderate at BayesDel <=-0.008, with no predicted splicing difference.
  • The case BayesDel score is 0.579613, above both TP53 VCEP benign thresholds; therefore BP4 is not met.
  • The case SpliceAI maximum delta is 0.004, but SpliceAI cannot substitute for the missense REVEL/BayesDel path or provide BP4 support for the amino-acid substitution.
  • The exact TP53 VCEP lookup row c.527G>T / p.Cys176Phe assigns PP3_moderate and does not assign BP4.
Still missing
  • No c.527G>T, p.Cys176Phe, or p.C176F entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx; that deletion-specific table is not applicable to this missense variant.
Sources
cspec ↗vcep_pp3_bp4_codesbayesdelspliceai ↗
BP7 N/ANot applicable: c.527G>T is a missense variant producing p.Cys176Phe, whereas BP7 is restricted to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_000546.6:c.527G>T produces the missense substitution p.Cys176Phe (p.C176F), so BP7 is outside its criterion scope and is not evaluated.

Rule
TP53 VCEP BP7 scope: synonymous or qualifying intronic variants only.
Evidence considered
  • The TP53 VCEP BP7 rule applies to synonymous or intronic variants, not missense substitutions.
  • Case normalization identifies c.527G>T as the missense substitution p.Cys176Phe / p.C176F.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.951. BayesDel score = 0.579613.

7 paper records listed. 1 cited in the classification.

Cited in the classification

  • TP53 disruptive mutations lead to head and neck cancer treatment failure through
    The paper explicitly studied TP53 C176F in HNSCC models and classified it as a disruptive TP53 mutation. In p53-null UMSCC1 cells, C176F expression produced relative radioresistance compared with wild-type and nondisruptive TP53 controls; C176F-expressing cells also showed no radiation-induced p21 induction.
    → PS3 · moderate Names this variant
    PMID 22090360 ↗
    Source detail
    Disruptive TP53 expressing UMSCC1 cells were found to be radioresistant relative to wild type TP53 and nondisruptive TP53 expressing cells.

    Location Results, paragraph 2 of 'Disruptive TP53 mutations are associated with p53-mediated radioresistance'; Figure 2

    Context TP53 constructs were expressed in p53-null UMSCC1 cells; endogenous p53 was silenced in HNSCC cell lines including HN 31 cells carrying C176F. Radiosensitivity was measured by clonogenic survival after irradiation, with p21 assessed by immunoblotting and reporter activity.

Other recorded publications

  • Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.
    Bullock AN et al. · 2000
    The paper identifies Cys176 as a zinc-ligand residue in the TP53 core domain and describes tumorigenic mutations at the zinc-binding site as minor cancer-associated hotspots; C176F was not one of the experimentally tested mutants.
    Does not name this variant
    PMID 10713666 ↗
    Quoted passage
    Tumorigenic mutations at the zinc-binding site (residues Cys 176, His 179, Cys 238 and Cys 242) occur as minor hotspots in comparison with R175H, which is the most common structural p53 mutation in cancer.

    Results, "Other mutations in the DNA-binding region"

  • Rescuing the function of mutant p53.
    Bullock AN et al. · 2001
    No paper-specific finding is recorded.
    PMID 11900253 ↗
  • Complex functions of mutant p53 alleles from human prostate cancer.
    Shi XB et al. · 2002
    No paper-specific finding is recorded.
    PMID 11920959 ↗
  • Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
    Kato S et al. · 2003
    No paper-specific finding is recorded.
    PMID 12826609 ↗
  • A global suppressor motif for p53 cancer mutants.
    Baroni TE et al. · 2004
    The paper explicitly names C176F as a TP53 zinc-binding-site mutation and groups it with mutations associated with global denaturation and a need for increased stability and DNA binding; it does not establish a separate Cys176 comparator or a VCEP PM1 threshold.
    Names this variant
    PMID 15037740 ↗
    Quoted passage
    Mutations affecting the zinc-binding site are one such group (R175H, C176F, H179R, and H179Y), which is consistent with the assessment that such mutants are globally denatured and require increased stability and DNA binding for rescue (8, 31).

    Discussion, paragraph beginning "Our data also suggests several types of p53 mutations that may not be rescued by the suppressor motif."

  • Prediction of TP53 status for primary cisplatin, fluorouracil, and leucovorin chemotherapy in ethmoid sinus intestinal-type adenocarcinoma.
    Licitra L et al. · 2004
    This paper explicitly reports TP53 Cys176Phe (TGC>TTC), corresponding to c.527G>T/p.C176F, in three patients with ethmoid intestinal-type adenocarcinoma. The variants were identified by sequencing pretreatment tumor biopsies in a 30-patient cohort, and the patients had residual disease after chemotherapy; the report does not establish germline status or provide a TP53 VCEP LFS cancer-point tally.
    Names this variant
    PMID 15611505 ↗
    Quoted passage
    Missense mutation ex 5, Cys176Phe/TGC→TTC Mutated Disabling

    Table 1, case numbers 24, 27, and 28; Results section

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,614,238 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.004 Open source ↗
ClinVar 2 Likely pathogenic · 1 Likely Pathogenic · 1 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

This variant is present in gnomAD v4.1 (AF= 1.23897e-06; MAF= 0.00012%, 2/1614238 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69485e-06; MAF= 0.00017%, 2/1180046 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97956e-06; MAF= 0.00040%, 1/251284 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80297e-06; MAF= 0.00088%, 1/113598 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory). (ClinVarID = 376569)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.951. BayesDel score = 0.579613.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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; COSV52661329, n = 343 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.