Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
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Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
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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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
VUS: no adjudicated criteria contribute points under the ClinGen TP53 VCEP v2.4 point-based framework, yielding a total of 0 points.
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
22 / 398,680 alleles
gnomAD v4.1: 22 / 398,680 alleles. Recorded AF 5.51821e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000223001; MAF= 0.02230%, 7/31390 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000453779; MAF= 0.04538%, 7/15426 alleles, homozygotes = 0); grpmax FAF= 0.00021217.
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.
28 criteria with recorded statuses: 0 met · 3 not met · 6 not assessed · 19 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All three requested criteria are not applicable because NM_000546.6:c.-89A>G is a 5′-UTR single-nucleotide variant with p.? and no qualifying protein-length or null-variant consequence.
The governing TP53 VCEP PVS1 files were searched for c.-89A>G and the requested p.? notations; no exact pre-assigned entry was found.
The ClinGen TP53 VCEP v2.4 framework governs all four requested criteria.
PS2, PP1, and BS4 cannot be assessed because the case contains no proband, parental, pedigree, relative-genotype, phenotype, or meiosis evidence.
PM6 is not applicable because the TP53 VCEP explicitly dropped PM6 and directs de novo evidence to PS2.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched under c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found.
All three requested computational criteria are not_applicable because NM_000546.6:c.-89A>G is a 5' UTR variant with protein consequence p.?, not a missense, synonymous, intronic, or splice-region variant within the applicable TP53 VCEP rules.
The ClinGen TP53 VCEP v2.4 framework governs all four requested criteria.
Population frequency evidence does not meet BA1, BS1, or PM2 because the relevant gnomAD v4.1 frequencies exceed the TP53 PM2 limit but remain below the TP53 BS1 and BA1 limits.
BS2 is not assessable because no individual-level unaffected older female carrier data are available.
No criteria match.
Not met · 3 · evaluated, threshold not reached
PM2Not met: gnomAD v4.1 total AF is 0.0000551821, above the TP53 VCEP PM2 limit of 0.00003.
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Reasoning
The governing ClinGen TP53 VCEP v2.4 applies PM2 only at supporting strength and requires total allele frequency below 0.00003 in gnomAD or another large sequenced population; if multiple alleles are present in an ancestry group, that group's frequency must be below 0.00004. gnomAD v4.1 reports total AF 0.0000551821 (22/398,680 alleles), and the maximum ancestry-group FAF is 0.00005467, exceeding both VCEP limits. European non-Finnish AF is 0.000084030 (19/226,110), also above the ancestry-group limit. Although the gnomAD v2.1 non-cancer exome subset has 0/0 exome alleles and is uninformative, the VCEP does not require a non-cancer or exome-only source; the default all-comers gnomAD v4.1 data therefore govern. No homozygotes are observed, but zero homozygotes does not overcome the frequency thresholds.
Rule
TP53 VCEP v2.4: PM2 supporting requires AF <0.00003 in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group's AF must be <0.00004.
Evidence considered
The TP53 VCEP v2.4 PM2 rule requires total AF <0.00003; when multiple alleles are present in an ancestry group, that group's AF must be <0.00004; PM2 is supporting only.
gnomAD v4.1 all-comers reports AF 0.0000551821 (22/398,680 alleles), maximum ancestry-group FAF 0.00005467, and European non-Finnish AF 0.000084030 (19/226,110), exceeding the applicable PM2 limits.
The gnomAD v2.1 non-cancer exome subset reports 0/0 exome alleles and is uninformative; the TP53 VCEP does not specify a non-cancer or exome-only population source, so the default all-comers gnomAD v4.1 data are used.
No homozygotes are observed in gnomAD v4.1, but this does not negate the allele-frequency threshold failure.
BA1Not met: the highest eligible non-founder gnomAD v4.1 FAF is 0.000084030, below the TP53 VCEP BA1 threshold of 0.001.
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Reasoning
The governing ClinGen TP53 VCEP v2.4 requires a filtering allele frequency (FAF) of at least 0.001 in a single eligible gnomAD continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles. In gnomAD v4.1, Finnish individuals have FAF 0.000146692 (2/31,446) but are a founder-effect group excluded by the rule; the highest eligible non-founder continental group is European non-Finnish at 0.000084030 (19/226,110), below 0.001. The all-comers gnomAD v4.1 total AF is 0.0000551821 (22/398,680), also far below the VCEP BA1 threshold, and no homozygotes are observed.
Rule
TP53 VCEP v2.4: BA1 stand-alone requires filtering allele frequency (FAF) >=0.001 in an eligible gnomAD continental subpopulation of one ancestry group, with >=2,000 alleles tested and >=2 alleles present.
Evidence considered
The TP53 VCEP v2.4 BA1 rule requires FAF >=0.001 in one eligible continental ancestry group, with >=2,000 alleles tested and >=2 variant alleles; founder-effect groups are excluded.
gnomAD v4.1 reports 2/31,446 alleles in Finnish individuals (AF 0.0000636011; FAF 0.000146692), and 19/226,110 alleles in European non-Finnish individuals (AF 0.000084030); neither reaches 0.001.
gnomAD v4.1 all-comers reports AF 0.0000551821 (22/398,680 alleles) and zero homozygotes.
BS1Not met: the highest eligible non-founder gnomAD v4.1 FAF is 0.000084030, below the TP53 VCEP BS1 lower threshold of 0.0003.
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Reasoning
The governing ClinGen TP53 VCEP v2.4 requires FAF >=0.0003 but <0.001 in one eligible continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles. Finnish individuals have FAF 0.000146692 but are a founder-effect group excluded by the rule; the highest eligible non-founder continental group is European non-Finnish at 0.000084030, below 0.0003. The older gnomAD v2.1 observation also does not establish BS1 because its reported group maximum FAF is 0.00021217, below the VCEP cutoff. No homozygotes are observed.
Rule
TP53 VCEP v2.4: BS1 strong requires filtering allele frequency (FAF) >=0.0003 and <0.001 in an eligible gnomAD continental subpopulation of one ancestry group, with >=2,000 alleles tested and >=2 alleles present.
Evidence considered
The TP53 VCEP v2.4 BS1 rule requires FAF >=0.0003 and <0.001 in one eligible continental ancestry group, with >=2,000 alleles tested and >=2 alleles present; founder-effect groups are excluded.
gnomAD v4.1 reports a maximum eligible FAF of 0.000146692 in Finnish individuals (2/31,446) and 0.000084030 in European non-Finnish individuals (19/226,110), both below 0.0003.
gnomAD v2.1 reports group maximum FAF 0.00021217, also below 0.0003; its highest observed European non-Finnish AF is 0.000453779 (7/15,426), but the VCEP rule is calibrated to FAF rather than raw AF.
PS2Not assessed: no proband phenotype or confirmed maternity-and-paternity de novo observation is available to calculate the TP53 VCEP PS2 points.
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Reasoning
The governing TP53 VCEP v2.4 applies PS2 exclusively to confirmed de novo evidence, with maternity and paternity confirmed, and requires de novo points to be tallied by the LFS cancer type in the Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf. The available case evidence contains no proband phenotype, parental testing, maternity or paternity confirmation, constitutional mosaicism documentation, or de novo observation. The governing table was searched for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found. PS2 therefore cannot be assessed.
Rule
TP53 VCEP v2.4 PS2: de novo points require confirmed maternity and paternity and are tallied by proband LFS cancer type; 1 point = Supporting, 2-3 = Moderate, 4-7 = Strong, and >=8 = Very Strong.
Evidence considered
The TP53 VCEP v2.4 PS2 rule states that the VCEP has dropped PM6 and uses PS2 exclusively for de novo evidence.
The TP53 VCEP v2.4 PS2 rule requires maternity and paternity confirmation and instructs curators to tally de novo points according to the proband cancer type.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf assigns PS2 Supporting at 1 point, Moderate at 2-3 points, Strong at 4-7 points, and Very Strong at >=8 points.
The case evidence provides no proband phenotype, parental testing, maternity or paternity confirmation, constitutional mosaicism evidence, or de novo observation.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-Code-Application.pdf was searched for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found.
Still missing
No proband phenotype, LFS-associated cancer type, or family-history information is available.
Parental testing and explicit confirmation of both maternity and paternity are unavailable.
No variant-specific entry was found after searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?.
No de novo point total can be calculated without the missing clinical and parental evidence.
PS4Not assessed: no proband phenotype, tumor pathology, or PS4 point total is available to compare with the 1-point Supporting threshold.
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Reasoning
The TP53 VCEP PS4 rule assigns points from proband clinical criteria and tumor pathology: Revised Chompret 0.5 point, Classic LFS 1 point, or HER2-positive breast cancer diagnosed before age 40 0.5 point, with PS4 Supporting at 1-1.5 points, Moderate at 2-3.5, Strong at 4-7.5, and Very Strong at >=8 points. The case evidence contains no proband phenotype, cancer history, tumor HER2 status, or point total for NM_000546.6:c.-89A>G. The required exact-variant searches found no entry in PS4-Points-Table.pdf.txt for c.-89A>G or p.?, and this table is a scoring table rather than an exact-variant classification table.
Rule
TP53 VCEP PS4: Revised Chompret = 0.5 point; Classic LFS = 1 point; HER2-positive breast cancer below age 40 = 0.5 point; Supporting = 1-1.5 points, Moderate = 2-3.5 points, Strong = 4-7.5 points, Very Strong >= 8 points.
Evidence considered
The TP53 VCEP Version 2.4 PS4 specification assigns 0.5 point for Revised Chompret criteria, 1 point for Classic LFS criteria, and 0.5 point for HER2-positive breast cancer diagnosed below age 40.
The TP53 VCEP PS4 thresholds are Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, and Very Strong >=8 points.
The consolidated case evidence reports no phenotype or tumor-pathology observations from which PS4 points can be calculated.
The required exact-variant search of /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/TP53/fulltext/PS4-Points-Table.pdf.txt found no c.-89A>G or p.? entry.
Still missing
No proband cancer phenotype or Revised Chompret/Classic LFS status is available for NM_000546.6:c.-89A>G.
No tumor HER2 status or age at breast-cancer diagnosis is available.
No exact-variant entry was found when PS4-Points-Table.pdf.txt was searched for c.-89A>G or p.?.
PP1Not assessed: no informative relatives or meioses are available to compare variant carriage with LFS-associated cancer status.
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Reasoning
The governing TP53 VCEP v2.4 requires observed cosegregation for PP1: 3-4 meioses for Supporting, 5-6 meioses for Moderate, or at least 7 meioses across more than one family for Strong. The available case evidence contains no relatives, genotypes, affected-status information, inheritance phase, or meioses. The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found. PP1 cannot be assessed.
Rule
TP53 VCEP v2.4 PP1: cosegregation in 3-4 meioses = Supporting, 5-6 meioses = Moderate, and >=7 meioses across more than one family = Strong.
Evidence considered
The TP53 VCEP v2.4 PP1 rule requires 3-4 cosegregating meioses for Supporting, 5-6 for Moderate, or >=7 across more than one family for Strong.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf defines LFS-associated cancer categories to use when evaluating family evidence.
The case evidence contains no relatives, genotypes, affected-status information, inheritance phase, or informative meioses.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found.
Still missing
No family pedigree or list of tested relatives is available.
No relative-level genotypes, phenotype status, phase information, or informative meiosis count is available.
No variant-specific entry was found after searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?.
A PP1 assessment requires documented cosegregation across informative meioses and, for PP1 Strong, more than one family.
PP4Not assessed: no multigene-panel VAF observation is available to compare with the TP53 PP4 5-35% Supporting range.
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Reasoning
The TP53 VCEP PP4 rule is applicable to low-variant-allele-fraction TP53 findings from multigene panel testing: at least two independent observations with VAF 5-25% support Moderate, and an observation with VAF 5-35% supports Supporting. The case evidence provides no multigene-panel context, no patient phenotype, and no VAF observation for NM_000546.6:c.-89A>G, so the required VAF comparison cannot be performed.
Rule
TP53 VCEP PP4: at least 2 independent observations with VAF 5-25% = Moderate; observation with VAF 5-35% = Supporting; do not apply if the low-VAF finding is in a patient with blood cancer, if BA1 or BS1 is met, or without multigene-panel detection.
Evidence considered
The TP53 VCEP PP4 specification requires an observation from multigene panel testing with VAF 5-35% for Supporting or at least two independent observations with VAF 5-25% for Moderate.
The case evidence contains no VAF, multigene-panel observation, or phenotype data for NM_000546.6:c.-89A>G; therefore no numeric inequality is available to evaluate.
Still missing
No multigene-panel testing context is available.
No VAF value or independent low-VAF observations are available for this variant.
No phenotype or tissue-confirmation information is available to evaluate the TP53 PP4 caveats.
BS2Not assessed: no source provides the required count of unrelated female carriers aged at least 60 years without cancer.
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Reasoning
The TP53 VCEP v2.4 BS2 rule requires 2-3 unrelated females aged at least 60 years without cancer for supporting, 4-7 for moderate, or at least 8 for strong, with all individuals from one source and with late sarcoma cases excluded. The available population data provide allele counts, frequencies, and homozygote counts but do not identify unaffected female carriers, ages, cancer histories, source-level independence, or sarcoma histories. Therefore BS2 cannot be adjudicated from the available evidence.
Rule
TP53 VCEP v2.4: BS2 supporting requires 2-3 unrelated females aged >=60 years without cancer from one source; moderate requires 4-7 and strong requires >=8, with late sarcoma cases excluded.
Evidence considered
The TP53 VCEP v2.4 BS2 rule requires 2-3 unrelated females aged >=60 years without cancer for supporting, 4-7 for moderate, or >=8 for strong, all from one source; late sarcoma cases do not count.
gnomAD v4.1 reports zero homozygotes but does not provide the individual-level age, sex, cancer-history, independence, and sarcoma-exclusion information required for BS2.
Still missing
A single source containing identifiable unrelated female carriers is needed.
For each carrier, age >=60 years, absence of cancer, and exclusion of sarcoma diagnosed at >=61 years must be documented.
BS4Not assessed: no affected family members with documented non-carriage of the variant are available for the TP53 VCEP BS4 Strong rule.
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Reasoning
The governing TP53 VCEP v2.4 permits BS4 Strong for lack of segregation in affected family members diagnosed with LFS-associated cancers listed in the Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf, while cautioning that phenocopies and multiple pathogenic variants can confound interpretation. The available case evidence contains no affected family members, family genotypes, phenotype records, or non-segregation observations. BS4 cannot be assessed.
Rule
TP53 VCEP v2.4 BS4: Strong applies for lack of segregation in affected family members with LFS-associated cancers listed in the governing LFS cancer table.
Evidence considered
The TP53 VCEP v2.4 BS4 rule applies Strong evidence to lack of segregation in affected family members diagnosed with LFS-associated cancers.
The TP53 VCEP v2.4 cautions that phenocopies and more than one pathogenic variant in a family can confound an apparent lack of segregation.
The case evidence contains no affected family members, family genotypes, phenotype records, or non-segregation observations.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found.
Still missing
No affected family members or LFS-associated cancer diagnoses are documented.
No family-member genotypes demonstrating absence of the variant are available.
No information is available to evaluate phenocopies or the possibility of more than one pathogenic variant in the family.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found.
Not applicable · 19· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.-89A>G is a 5′-UTR p.? variant, and SpliceAI max delta 0.072 does not indicate a qualifying splice-loss null consequence.
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Reasoning
Not applicable: NM_000546.6:c.-89A>G is a 5′-UTR sequence variant with NP_000537.3:p.? and is not a nonsense, frameshift, canonical ±1,2 splice-site, initiation-codon, or copy-number null variant covered by the TP53 PVS1 flowchart. SpliceAI reports a maximum delta of 0.072, below the VCEP's 0.2 no-impact boundary, so there is no predicted splice consequence that would convert this noncoding variant into a PVS1-applicable loss-of-function event. The exact variant was searched in both governing files and no pre-assigned entry was found.
Rule
TP53 VCEP PVS1 flowchart applicability; non-null 5′-UTR variant with no qualifying splice consequence
Evidence considered
The TP53 VCEP PVS1 flowchart for NM_000546.6 limits PVS1 to defined null-variant mechanisms, including nonsense, frameshift, canonical splice-site, initiation-codon, and copy-number events; this c.-89 5′-UTR variant is none of those.
The case normalization is NP_000537.3:p.? and the variant assessment identifies no canonical splice consensus consequence.
SpliceAI maximum delta is 0.072, below the TP53 VCEP no-significant-splice-impact boundary of 0.2.
Exact-notation searches for c.-89A>G, p.?, and p.? found no entry in either governing PVS1 file.
Still missing
No exact c.-89A>G, p.?, or p.? entry was found in PVS1-Flowchart.pdf.txt.
No exact c.-89A>G, p.?, or p.? entry was found in PVS1-Splicing-Worksheet.xlsx.txt.
PS1N/ANot applicable: c.-89A>G has protein consequence p.? rather than a missense amino-acid substitution required for same-residue PS1.
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Reasoning
The governing TP53 VCEP version 2.4 permits PS1 for a variant asserted as pathogenic under the TP53 specifications, but this variant is NM_000546.6:c.-89A>G with protein consequence p.? and is not a missense substitution; therefore no same-amino-acid change can be evaluated for PS1.
Rule
Can be applied to variants asserted as Pathogenic following the TP53 VCEP’s specifications.
Evidence considered
The TP53 VCEP version 2.4 PS1 rule applies to variants asserted as pathogenic following TP53 specifications.
The case variant is NM_000546.6:c.-89A>G with normalized protein consequence NP_000537.3:p.? and unknown consequence class, so no amino-acid change exists for same-residue comparison.
PS3N/ANot applicable: the VCEP functional framework covers missense variants and small in-frame deletions, whereas c.-89A>G is an upstream noncoding substitution with p.?.
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Reasoning
The TP53 VCEP functional framework applies PS3 to missense variants and small in-frame deletions using protein-function assays. NM_000546.6:c.-89A>G is an upstream noncoding substitution, normalized as NP_000537.3:p.?, and therefore has no amino-acid change to evaluate in the governing functional worksheet. Searches found no entry for c.-89A>G, p.?, or its genomic coordinates in the Functional-worksheet.xlsx text. PS3 is not applicable rather than not assessed.
Rule
Not applicable: the TP53 VCEP PS3 functional specification is for missense variants and small in-frame deletions.
Evidence considered
The TP53 VCEP functional flowchart limits this functional-rule pathway to missense variants and small in-frame deletions.
The TP53 VCEP specifies PS3 for non-functional or partially functional protein assay results, with assay-specific strength calibration, but this upstream noncoding substitution produces p.? and is outside that scope.
The full Functional-worksheet.xlsx text was searched for c.-89A>G, p.?, c.-89, 17-7590755, and 17-7687437; no variant-specific row was found.
Case normalization identifies NM_000546.6:c.-89A>G as upstream of the coding sequence and predicts NP_000537.3:p.?.
Still missing
No entry for c.-89A>G, p.?, or the corresponding genomic coordinates was found in Functional-worksheet.xlsx.
No variant-specific functional assay entry was found in Flowchart-for-application-of-functional-rule-codes.pdf.
PM1N/ANot applicable: c.-89A>G has no encoded residue, so it cannot be assessed against TP53 PM1 hotspot codons or a functional domain.
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Reasoning
The governing TP53 VCEP version 2.4 PM1 rule is restricted to missense variants at codons 175, 245, 248, 249, 273, or 282, or to specified cancer-hotspot same-amino-acid changes. This c.-89A>G variant has protein consequence p.? and no residue to compare with those codons; vcep_materials.json also contains no domain-table entries for TP53.
Rule
Missense variants within codons 175, 245, 248, 249, 273, or 282; or cancerhotspots.org same-amino-acid changes with 2-9 or at least 10 somatic occurrences according to the specified strength.
Evidence considered
The TP53 VCEP version 2.4 PM1 moderate rule lists codons 175, 245, 248, 249, 273, and 282; its supporting rule concerns cancerhotspots.org same-amino-acid occurrences.
The variant is NM_000546.6:c.-89A>G with protein consequence NP_000537.3:p.? and therefore has no residue coordinate; the authoritative domain_tables object for TP53 is empty.
PM3VCEPNot applicable: the TP53 VCEP version 2.4 explicitly designates PM3 as Not Applicable.
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Reasoning
The governing ClinGen TP53 VCEP specification, version 2.4, explicitly designates PM3 as Not Applicable; therefore recessive allelic evidence such as affected probands, phase, and pathogenic variants in trans is not used for this TP53 assessment.
VCEP rule
ClinGen TP53 VCEP version 2.4: PM3 Not Applicable.
Evidence considered
The ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines, version 2.4, lists PM3 with applicability set to Not Applicable.
The framework's disease model is autosomal dominant Li-Fraumeni syndrome, and no PM3 trans-phase assessment is permitted under the governing specification.
PM4VCEPNot applicable: the single-nucleotide 5′-UTR variant has p.? and causes no documented protein length change.
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Reasoning
Not applicable: PM4 concerns abnormal protein length caused by an in-frame deletion or protein-length-changing indel. NM_000546.6:c.-89A>G is a single-nucleotide 5′-UTR variant with predicted protein consequence p.?, so it neither removes nor adds amino acids and cannot meet PM4.
VCEP rule
TP53 VCEP PM4 applicability: not applicable
Evidence considered
The TP53 VCEP specification marks PM4 as Not Applicable.
The normalized protein consequence is NP_000537.3:p.? for a c.-89 5′-UTR single-nucleotide substitution, with no amino-acid deletion, insertion, or extension identified.
PM5N/ANot applicable: c.-89A>G has protein consequence p.? and is not a missense variant eligible for same-residue PM5 comparison.
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Reasoning
The governing TP53 VCEP version 2.4 PM5 rules require a missense variant at an amino-acid residue where a different pathogenic or clinically supported likely pathogenic missense variant has previously been observed. NM_000546.6:c.-89A>G has protein consequence p.? and is not a missense variant, so same-residue comparator evidence cannot apply.
Rule
Missense variant at an amino-acid residue where at least 2 different missense variants previously determined pathogenic, 1 pathogenic variant, or 1 clinically supported likely pathogenic variant has been seen before, according to the TP53 VCEP specifications.
Evidence considered
The TP53 VCEP version 2.4 PM5 rules require a missense variant and a different missense variant at the same amino-acid residue with the specified pathogenicity evidence.
The case variant is annotated NP_000537.3:p.? with unknown consequence class, so no amino-acid residue or missense comparator can be defined.
PM6VCEPNot applicable: the TP53 VCEP v2.4 explicitly drops PM6 and directs all de novo evidence to the PS2 framework.
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Reasoning
PM6 is not applicable under the governing TP53 VCEP v2.4 specification. The specification explicitly states that PM6 is dropped and that de novo evidence, including cases without complete parental confirmation, is handled under the PS2 combined rule rather than PM6.
VCEP rule
TP53 VCEP v2.4: PM6 is not applicable; de novo evidence is evaluated under PS2 exclusively.
Evidence considered
The TP53 VCEP v2.4 PS2 instruction states: the VCEP has opted to drop PM6 and use PS2 exclusively for de novo evidence.
The TP53 VCEP v2.4 PM6 entry is marked not applicable and refers to the PS2/PM6 combined rule.
PP2VCEPNot applicable: the TP53 VCEP marks PP2 not applicable, and c.-89A>G has no missense protein consequence.
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Reasoning
The governing TP53 VCEP version 2.4 explicitly marks PP2 as not applicable. Independently, this variant has protein consequence p.? rather than a missense consequence, so the gene-level missense mechanism criterion cannot be applied.
VCEP rule
Not Applicable.
Evidence considered
The TP53 VCEP version 2.4 framework explicitly lists PP2 as Not Applicable.
The variant is NM_000546.6:c.-89A>G with normalized protein consequence NP_000537.3:p.?, not a missense substitution.
PP3N/ANot applicable: c.-89A>G is a 5' UTR variant with p.?, outside PP3's missense and intronic/splice-region scope; SpliceAI 0.072 is therefore not evaluated.
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Reasoning
PP3 is not applicable. NM_000546.6:c.-89A>G is a 5' untranslated-region variant with protein consequence p.?; it is neither missense nor an intronic or splice-region variant within the scope of the TP53 VCEP PP3 rule. The governing TP53 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched for c.-89A>G and p.?; no entry for this variant was found. Because the criterion is out of scope, the available SpliceAI max delta of 0.072 was not used to assess PP3.
Evidence considered
The TP53 VCEP framework defines PP3 for missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants; c.-89A>G has protein consequence p.? and is a 5' UTR variant.
The consolidated case evidence identifies NM_000546.6:c.-89A>G as p.? and reports SpliceAI max delta 0.072, but predictor evaluation is not reached for an out-of-scope PP3 variant.
The three declared TP53 in-silico files were searched for c.-89A>G and p.?; no governing pre-assigned entry was found.
Still missing
No c.-89A>G or p.? entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No c.-89A>G or p.? entry was found in PP3-BP4-codes.xlsx.txt.
No c.-89A>G or p.? entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
PP5VCEPNot applicable: the TP53 VCEP excludes PP5, and ClinVar has no exact-variant expert-panel classification.
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Reasoning
The TP53 VCEP Version 2.4 explicitly marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar contains no exact-variant record or expert-panel classification for NM_000546.6:c.-89A>G.
VCEP rule
TP53 VCEP PP5: not applicable; do not use.
Evidence considered
The TP53 VCEP PP5 specification says: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
ClinVar reports no exact-variant record, expert-panel classification, or other classification for NM_000546.6:c.-89A>G.
BS3N/ANot applicable: the VCEP functional framework covers missense variants and small in-frame deletions, whereas c.-89A>G is an upstream noncoding substitution with p.?.
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Reasoning
The TP53 VCEP functional framework applies BS3 to missense variants and small in-frame deletions using protein-function assays. NM_000546.6:c.-89A>G is an upstream noncoding substitution, normalized as NP_000537.3:p.?, and therefore has no amino-acid change to evaluate in the governing functional worksheet. Searches found no entry for c.-89A>G, p.?, or its genomic coordinates in the Functional-worksheet.xlsx text. BS3 is not applicable rather than not assessed.
Rule
Not applicable: the TP53 VCEP BS3 functional specification is for missense variants and small in-frame deletions.
Evidence considered
The TP53 VCEP functional flowchart limits this functional-rule pathway to missense variants and small in-frame deletions.
The TP53 VCEP specifies BS3 for functional or partially functional protein assay results meeting its Kato and eligible-assay requirements, but this upstream noncoding substitution produces p.? and is outside that scope.
The full Functional-worksheet.xlsx text was searched for c.-89A>G, p.?, c.-89, 17-7590755, and 17-7687437; no variant-specific row was found.
Case normalization identifies NM_000546.6:c.-89A>G as upstream of the coding sequence and predicts NP_000537.3:p.?.
Still missing
No entry for c.-89A>G, p.?, or the corresponding genomic coordinates was found in Functional-worksheet.xlsx.
No variant-specific functional assay entry was found in Flowchart-for-application-of-functional-rule-codes.pdf.
BP1VCEPNot applicable: the TP53 VCEP marks BP1 not applicable, and c.-89A>G is not a missense variant with a defined residue.
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Reasoning
The governing TP53 VCEP version 2.4 explicitly marks BP1 as not applicable. This variant also has protein consequence p.? rather than a missense consequence, so a benign evidence code for a missense variant outside a critical region cannot be applied.
VCEP rule
Not Applicable.
Evidence considered
The TP53 VCEP version 2.4 framework explicitly lists BP1 as Not Applicable.
The variant is NM_000546.6:c.-89A>G with normalized protein consequence NP_000537.3:p.?, not a missense substitution.
BP2VCEPNot applicable: the TP53 VCEP version 2.4 explicitly designates BP2 as Not Applicable.
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Reasoning
The governing ClinGen TP53 VCEP specification, version 2.4, explicitly designates BP2 as Not Applicable; therefore observations of this variant in cis with a pathogenic variant or in trans with a benign variant are not used for this TP53 assessment.
VCEP rule
ClinGen TP53 VCEP version 2.4: BP2 Not Applicable.
Evidence considered
The ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines, version 2.4, lists BP2 with applicability set to Not Applicable.
Because BP2 is excluded by the governing TP53 framework, phase and co-occurrence observations cannot be used to apply this criterion.
BP3VCEPNot applicable: c.-89A>G is a 5′-UTR single-nucleotide substitution, not an in-frame deletion in a repetitive protein region.
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Reasoning
Not applicable: BP3 is a benign criterion for an in-frame deletion in a repetitive region. NM_000546.6:c.-89A>G is a 5′-UTR single-nucleotide substitution with p.? and is not an in-frame protein deletion or a repeat-region protein indel.
VCEP rule
TP53 VCEP BP3 applicability: not applicable
Evidence considered
The TP53 VCEP specification marks BP3 as Not Applicable.
The variant is a 5′-UTR single-nucleotide substitution with normalized protein consequence p.?, not an in-frame deletion.
BP4N/ANot applicable: c.-89A>G is a 5' UTR variant with p.?, outside BP4's missense and intronic/splice-region scope; SpliceAI 0.072 is therefore not evaluated.
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Reasoning
BP4 is not applicable. NM_000546.6:c.-89A>G is a 5' untranslated-region variant with protein consequence p.?; it is neither missense nor an intronic or splice-region variant within the scope of the TP53 VCEP BP4 rule. The governing TP53 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched for c.-89A>G and p.?; no entry for this variant was found. Because the criterion is out of scope, the available SpliceAI max delta of 0.072 was not used to assess BP4.
Evidence considered
The TP53 VCEP framework defines BP4 for missense variants, single-amino-acid in-frame deletions, and silent or intronic variants; c.-89A>G has protein consequence p.? and is a 5' UTR variant.
The consolidated case evidence identifies NM_000546.6:c.-89A>G as p.? and reports SpliceAI max delta 0.072, but predictor evaluation is not reached for an out-of-scope BP4 variant.
The three declared TP53 in-silico files were searched for c.-89A>G and p.?; no governing pre-assigned entry was found.
Still missing
No c.-89A>G or p.? entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No c.-89A>G or p.? entry was found in PP3-BP4-codes.xlsx.txt.
No c.-89A>G or p.? entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
BP5VCEPNot applicable: the TP53 VCEP excludes BP5 and provides no governing alternate-molecular-basis rule for this case.
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Reasoning
The TP53 VCEP Version 2.4 marks BP5 as not applicable and provides no TP53-specific BP5 rule. The available case evidence contains no alternate molecular basis for disease that could independently support generic BP5, and the governing VCEP specification takes precedence.
VCEP rule
TP53 VCEP BP5: not applicable.
Evidence considered
The TP53 VCEP BP5 specification marks the criterion Not applicable and gives no applicable strength rule.
No alternate molecular basis for disease is documented in the consolidated case evidence, but BP5 remains excluded by the governing TP53 VCEP specification.
BP6VCEPNot applicable: the TP53 VCEP excludes BP6, and ClinVar has no exact-variant expert-panel benign classification.
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Reasoning
The TP53 VCEP Version 2.4 explicitly marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar contains no exact-variant expert-panel benign or likely-benign classification for NM_000546.6:c.-89A>G.
VCEP rule
TP53 VCEP BP6: not applicable; do not use.
Evidence considered
The TP53 VCEP BP6 specification says: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
ClinVar reports no exact-variant record, expert-panel classification, or other classification for NM_000546.6:c.-89A>G.
BP7N/ANot applicable: c.-89A>G is a 5' UTR variant with p.?, not synonymous; BP7 therefore does not apply regardless of the SpliceAI max delta 0.072.
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Reasoning
BP7 is not applicable. NM_000546.6:c.-89A>G is a 5' untranslated-region variant with protein consequence p.? and is not a synonymous variant, which is required for BP7 under the TP53 VCEP framework. The governing TP53 flowchart and PP3-BP4 lookup table were searched for c.-89A>G and p.?; no entry for this variant was found. The available SpliceAI max delta of 0.072 was not used because BP7 is out of scope.
Evidence considered
The TP53 VCEP BP7 rule applies to synonymous or silent variants and specified intronic variants; c.-89A>G has protein consequence p.? and is a 5' UTR variant.
The consolidated case evidence identifies NM_000546.6:c.-89A>G as p.? and reports SpliceAI max delta 0.072, but BP7 is not evaluated for this non-synonymous, non-intronic variant.
The three declared TP53 in-silico files were searched for c.-89A>G and p.?; no governing pre-assigned entry was found.
Still missing
No c.-89A>G or p.? entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No c.-89A>G or p.? entry was found in PP3-BP4-codes.xlsx.txt.
No c.-89A>G or p.? entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
AF 5.5e-05 · 22 / 398,680 alleles · 0 hom · FAF 5.5e-05
European (non-Finnish)19 / 226,110
8.4e-05
European (Finnish)2 / 31,446
6.4e-05
Remaining individuals1 / 18,490
5.4e-05
0 alternate alleles recorded in 7 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00022 · 7 / 31,390 alleles · 0 hom · FAF 0.00021
European (non-Finnish)7 / 15,426
0.00045
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= 5.51821e-05; MAF= 0.00552%, 22/398680 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.40299e-05; MAF= 0.00840%, 19/226110 alleles, homozygotes = 0); grpmax FAF= 5.467e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000223001; MAF= 0.02230%, 7/31390 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000453779; MAF= 0.04538%, 7/15426 alleles, homozygotes = 0); grpmax FAF= 0.00021217.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -469 bp
0.000
SpliceAI acceptor gainat -467 bp
0.000
SpliceAI donor lossat -60 bp
0.003
SpliceAI donor gainat +21 bp
0.072
Pangolin splice lossmagnitude shown
-0.052
Pangolin splice gain
0.007
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: c.-89A>G is a 5' UTR variant with p.?, outside PP3's missense and intronic/splice-region scope; SpliceAI 0.072 is therefore not evaluated.
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Reasoning
PP3 is not applicable. NM_000546.6:c.-89A>G is a 5' untranslated-region variant with protein consequence p.?; it is neither missense nor an intronic or splice-region variant within the scope of the TP53 VCEP PP3 rule. The governing TP53 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched for c.-89A>G and p.?; no entry for this variant was found. Because the criterion is out of scope, the available SpliceAI max delta of 0.072 was not used to assess PP3.
Evidence considered
The TP53 VCEP framework defines PP3 for missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants; c.-89A>G has protein consequence p.? and is a 5' UTR variant.
The consolidated case evidence identifies NM_000546.6:c.-89A>G as p.? and reports SpliceAI max delta 0.072, but predictor evaluation is not reached for an out-of-scope PP3 variant.
The three declared TP53 in-silico files were searched for c.-89A>G and p.?; no governing pre-assigned entry was found.
Still missing
No c.-89A>G or p.? entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No c.-89A>G or p.? entry was found in PP3-BP4-codes.xlsx.txt.
No c.-89A>G or p.? entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
BP4N/ANot applicable: c.-89A>G is a 5' UTR variant with p.?, outside BP4's missense and intronic/splice-region scope; SpliceAI 0.072 is therefore not evaluated.
Details ▾Hide ▴
Reasoning
BP4 is not applicable. NM_000546.6:c.-89A>G is a 5' untranslated-region variant with protein consequence p.?; it is neither missense nor an intronic or splice-region variant within the scope of the TP53 VCEP BP4 rule. The governing TP53 flowchart, PP3-BP4 lookup table, and single-amino-acid deletion BayesDel table were searched for c.-89A>G and p.?; no entry for this variant was found. Because the criterion is out of scope, the available SpliceAI max delta of 0.072 was not used to assess BP4.
Evidence considered
The TP53 VCEP framework defines BP4 for missense variants, single-amino-acid in-frame deletions, and silent or intronic variants; c.-89A>G has protein consequence p.? and is a 5' UTR variant.
The consolidated case evidence identifies NM_000546.6:c.-89A>G as p.? and reports SpliceAI max delta 0.072, but predictor evaluation is not reached for an out-of-scope BP4 variant.
The three declared TP53 in-silico files were searched for c.-89A>G and p.?; no governing pre-assigned entry was found.
Still missing
No c.-89A>G or p.? entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No c.-89A>G or p.? entry was found in PP3-BP4-codes.xlsx.txt.
No c.-89A>G or p.? entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
BP7N/ANot applicable: c.-89A>G is a 5' UTR variant with p.?, not synonymous; BP7 therefore does not apply regardless of the SpliceAI max delta 0.072.
Details ▾Hide ▴
Reasoning
BP7 is not applicable. NM_000546.6:c.-89A>G is a 5' untranslated-region variant with protein consequence p.? and is not a synonymous variant, which is required for BP7 under the TP53 VCEP framework. The governing TP53 flowchart and PP3-BP4 lookup table were searched for c.-89A>G and p.?; no entry for this variant was found. The available SpliceAI max delta of 0.072 was not used because BP7 is out of scope.
Evidence considered
The TP53 VCEP BP7 rule applies to synonymous or silent variants and specified intronic variants; c.-89A>G has protein consequence p.? and is a 5' UTR variant.
The consolidated case evidence identifies NM_000546.6:c.-89A>G as p.? and reports SpliceAI max delta 0.072, but BP7 is not evaluated for this non-synonymous, non-intronic variant.
The three declared TP53 in-silico files were searched for c.-89A>G and p.?; no governing pre-assigned entry was found.
Still missing
No c.-89A>G or p.? entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No c.-89A>G or p.? entry was found in PP3-BP4-codes.xlsx.txt.
No c.-89A>G or p.? entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
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= 5.51821e-05; MAF= 0.00552%, 22/398680 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.40299e-05; MAF= 0.00840%, 19/226110 alleles, homozygotes = 0); grpmax FAF= 5.467e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000223001; MAF= 0.02230%, 7/31390 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000453779; MAF= 0.04538%, 7/15426 alleles, homozygotes = 0); grpmax FAF= 0.00021217.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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