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This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About TP53
TP53 encodes the p53 protein, a critical tumor suppressor that acts as a transcription factor to protect cells from damage. When activated by cellular stress such as DNA damage, p53 triggers responses including DNA repair, cell cycle arrest, and programmed cell death (apoptosis) to prevent the propagation of damaged cells. TP53 is the most frequently mutated gene in human cancers, and loss of its function contributes to tumor development, invasion, drug resistance, and genomic instability. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a rare hereditary condition that greatly increases the risk of developing multiple types of cancer at a young age.
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.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 7 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Variant NM_000546.6:c.1001G>T / NP_000537.3:p.(Gly334Val) is a missense substitution.
ClinGen TP53 VCEP CSPEC v2.4 (cspec) is the governing framework and was consulted for all three criteria.
PVS1 is scoped to null variant classes per the TP53 VCEP PVS1 decision tree; this missense variant does not qualify, and the case's own pvs1_variant_assessment confirms this (apply_generic_pvs1_framework=false).
PM4 and BP3 are both explicitly flagged 'Not Applicable' for TP53 by the VCEP CSPEC, and independently do not apply to a missense substitution since it causes no protein length change and is not an in-frame indel.
PP2 and BP1 are explicitly Not Applicable under the TP53 VCEP specification and were not further assessed.
PS1 and PM5 require a same-amino-acid-change or same-residue comparator variant with a documented TP53 VCEP Pathogenic/Likely Pathogenic classification; no such comparator was found for p.Gly334Val or for other codon-334 substitutions (G334A/E/R), which only have VCEP functional (PS3/BS3) codes, not clinical classifications.
PM1 could not be formally assessed: codon 334 is outside the VCEP's explicit hotspot codon list, and while cancerhotspots.org and COSMIC both flag residue/variant-level recurrence, neither scrape result has a citable source_registry entry nor a verified same-amino-acid-change occurrence count meeting the VCEP's numeric threshold.
The applicable governing framework is the ClinGen TP53 Expert Panel specification version 2.4.
The bundle contains no proband phenotype, parental testing, family segregation, meiosis, or non-segregation evidence for this variant.
PS2, PP1, and BS4 therefore remain not assessed; PM6 is not applicable because the TP53 VCEP dropped PM6 in favor of PS2 exclusively for de novo evidence.
TP53 VCEP-specific functional rules (cspec v2.4) and the Functional-worksheet.xlsx (Supplementary Table S3) were used in preference to generic ACMG functional guidance, per the gene-specific curation protocol.
The pre-assigned VCEP functional code for NP_000537.3:p.(G334V) is PS3_Moderate, derived from Kato (Partially functional), Giacomelli (LOF), and Kawaguchi (Monomer/abnormal) assay classes; Funk and Kotler results are NA for this variant.
PS3 is met at Moderate strength; BS3 is not met, since the functional data is directionally pathogenic (partial loss of function), not benign.
Variant type is missense (p.Gly334Val), so the PP3/BP4 assessment follows the TP53 VCEP's aGVGD+BayesDel missense pathway, not the synonymous/intronic SpliceAI-only pathway (which governs BP7).
The TP53 VCEP's own pre-computed PP3-BP4-codes.xlsx spreadsheet (Supplementary Table S2) was consulted directly for this exact HGVS coding change and returns 'No evidence' as the preliminary bioinformatic code (aGVGD Class C15, BayesDel 0.56885), which was applied as-is per VCEP instruction to use pre-assigned codes directly.
SpliceAI max delta score = 0.00 confirms no predicted splicing impact, ruling out the exonic/intronic splice-effect branch of PP3 and confirming the splicing component of BP4 would be satisfied in isolation, but BP4 additionally requires a low BayesDel score which is not met.
BP7 is not applicable because the variant is missense, not synonymous or intronic.
No BayesDel publication with a verified/citable threshold independent of the VCEP-supplied spreadsheet was used; the VCEP's own gene-specific lookup table was treated as the authoritative pre-assigned source per instruction, since it is the governing VCEP's own supporting material.
Population evidence is limited to absence from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada; it supports PM2 at TP53 VCEP supporting strength but does not support BA1 or BS1.
BS2 cannot be assessed because the bundle contains no qualifying unaffected older-carrier series or homozygote observations.
No criteria match.
Met · 2
PS3ModerateMet (Moderate): p.Gly334Val is partially functional in Kato transactivation but shows loss of function in two other assays (Giacomelli, Kawaguchi).
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Reasoning
TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) gives a pre-assigned functional code of PS3_Moderate for p.G334V: Kato et al. transactivation class = Partially functional; Giacomelli et al. growth-suppression class = LOF; Kawaguchi et al. oligomerization class = Monomer (abnormal, i.e. not the wild-type Tetramer). Funk et al. and Kotler et al. classes are NA for this variant (not systematically covered/no distinct result reported). Applying the VCEP PS3 rule (Flowchart-for-application-of-functional-rule-codes.pdf / cspec functional instructions): 'Partially functional on Kato et al. data AND loss of function (LOF) by the majority of other available assays' -> of the two other assays with results (Giacomelli, Kawaguchi), both indicate LOF/abnormal function, satisfying 'majority of other available assays'. This meets the PS3_Moderate strength criterion. PVS1 is not applicable to this missense variant (pvs1_variant_assessment.json), so the VCEP caveat against combining full-strength PVS1 with PS3 does not apply. No literature paper in the case bundle reports variant-specific functional data for the exact NP_000537.3:p.(G334V) substitution (Kato 2003, Giacomelli 2018 full texts checked via paper_extracts and confirm no variant-specific text passage, consistent with the assay classes being drawn from the underlying high-throughput datasets summarized in the VCEP worksheet rather than the published prose).
Rule
TP53 VCEP PS3_Moderate: Partially functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays.
Evidence considered
Functional-worksheet.xlsx (Supplementary Table S3) row for G334V: Kato class = Partially functional; Funk class = NA; Giacomelli class = LOF; Kotler class = NA; Kawaguchi class = Monomer; Preliminary functional code = PS3_Moderate.
TP53 VCEP cspec PS3 rule (v2.4): 'Partially functional on Kato et al. data AND loss of function (LOF) by the majority of other available assays' = PS3_Moderate.
paper_extracts.json for PMID:12826609 (Kato et al. 2003) confirms full text does not name p.G334V specifically but establishes Gly-334 as a tetramerization-domain residue highly susceptible to functional inactivation by substitution, consistent with a partially-functional/LOF-prone classification at this position.
paper_extracts.json for PMID:30224644 (Giacomelli et al. 2018) confirms the MITE saturation-mutagenesis library covers all missense substitutions systematically but the published text does not report a variant-specific passage for p.G334V; the LOF class used here is the VCEP-curated dataset value.
pvs1_variant_assessment.json confirms this missense variant does not meet generic PVS1 null-variant buckets, so the VCEP caveat requiring PS3 downgrade/exclusion when PVS1 is applied at full strength is not triggered.
Still missing
No published paper full text explicitly discusses p.G334V by name; the Kato/Giacomelli/Kawaguchi classifications for this exact substitution come from the VCEP-curated Functional-worksheet.xlsx (Supplementary Table S3), which aggregates the underlying high-throughput/systematic datasets rather than variant-specific prose.
Funk et al. and Kotler et al. assay results are NA for G334V, limiting the assay count contributing to the 'majority of other available assays' determination to two (Giacomelli, Kawaguchi).
PM2SupportingMet (Supporting): the variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada population databases.
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Reasoning
PM2 is met at supporting strength under the TP53 VCEP. NM_000546.6:c.1001G>T (p.Gly334Val) is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0, consistent with an allele frequency below 0.00003 in a large sequenced population. No multiple-allele ancestry subgroup or low allele-balance artifact is documented, so no CHIP-related recalculation is needed from the available evidence.
Rule
TP53 VCEP v2.4 PM2: apply at supporting strength for allele frequency <0.00003 in gnomAD or another large sequenced population; if multiple alleles are present within an ancestry group, that group's frequency must be <0.00004; ignore founder-effect groups and consider allele-balance filtering for possible CHIP contamination.
Evidence considered
The TP53 VCEP version 2.4 requires PM2 to be applied at supporting strength when allele frequency is <0.00003 in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group's frequency must be <0.00004, and founder-effect groups are ignored.
The variant NM_000546.6:c.1001G>T (p.Gly334Val) is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0, providing population evidence compatible with PM2 supporting.
Still missing
The bundle reports absence but does not provide total allele counts, ancestry-specific counts, homozygote counts, or allele-balance histograms; these would be needed to independently verify the numeric upper-bound and evaluate low-VAF artifact handling.
PS1Not met: no other DNA change producing the same p.Gly334Val amino acid has been classified pathogenic or likely pathogenic.
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Reasoning
TP53 VCEP PS1 requires that a different nucleotide change producing the identical amino acid change (p.Gly334Val) has itself been classified Pathogenic (Strong) or Likely Pathogenic (Moderate) under the TP53 VCEP specifications. No such alternate-codon comparator producing p.Gly334Val was identified anywhere in the reviewed ClinVar, OncoKB, or literature sources; only this variant's own record was found (single-submitter 'Likely oncogenic' in ClinVar, not a TP53 VCEP classification). No qualifying comparator exists in the collected evidence.
Rule
TP53 VCEP PS1 (cspec v2.4): Strong if comparator variant with same amino acid change was classified Pathogenic by TP53 VCEP specs; Moderate if Likely Pathogenic.
Evidence considered
TP53 VCEP cspec v2.4 PS1 rule: apply Strong if a different nucleotide change giving the identical amino acid change has been asserted Pathogenic per TP53 VCEP specs; Moderate if asserted Likely Pathogenic.
ClinVar (VCV003764945) contains only this variant itself (single submitter, 'Likely oncogenic', not a TP53 VCEP classification), providing no independent same-amino-acid-change comparator for PS1.
Still missing
No alternate nucleotide substitution producing p.Gly334Val identified with a TP53 VCEP Pathogenic/Likely Pathogenic classification in the reviewed sources.
PM5Not met: no other substitution at codon 334 carries a formal pathogenic or likely pathogenic TP53 VCEP classification.
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Reasoning
TP53 VCEP PM5 requires a different missense substitution at the same residue (334) that has been determined Pathogenic (Strong for >=2 such variants, Moderate for 1) or Likely Pathogenic with supporting clinical data (Supporting) per TP53 VCEP specifications. Other substitutions at codon 334 exist in the VCEP functional worksheet: G334A (partially functional, LOF by tetramer assay, PS3_Moderate functional code), G334E (partially functional, no LOF, 'No evidence'), and G334R (functional, no LOF, BS3 functional code). These are functional-assay evidence codes (PS3/BS3), not documented overall TP53 VCEP clinical classifications of Pathogenic or Likely Pathogenic, so none satisfies the PM5 comparator requirement. PMID:32675277 and PMID:25584008 both describe G334R as a hypomorphic/partial-function germline variant (86.6% of wild-type transactivation activity; mildly impaired colony-suppression and tetramer stability) observed in pediatric adrenocortical carcinoma and other cancers with variable penetrance, but neither reports a formal Pathogenic/Likely Pathogenic clinical classification for G334R under TP53 VCEP rules; if anything the VCEP functional worksheet assigns G334R a benign-leaning BS3 functional code. No qualifying same-residue comparator variant was identified.
Rule
TP53 VCEP PM5 (cspec v2.4): Strong for >=2 prior pathogenic missense variants at the same residue, Moderate for 1 prior pathogenic, Supporting for 1 prior likely pathogenic variant with qualifying clinical data.
Evidence considered
TP53 VCEP cspec PM5 rule: Strong for >=2 different pathogenic missense variants at the same residue, Moderate for 1 pathogenic, Supporting for 1 likely pathogenic variant with qualifying clinical data (PS2/PS4/PP1).
VCEP functional worksheet (Supplementary Table S3) lists G334A as Partially functional/LOF/Tetramer/PS3_Moderate, G334E as Partially functional/noLOF/Monomer/No evidence, and G334R as Functional/noLOF/Tetramer/BS3 -- functional codes only, not clinical P/LP classifications.
PMID:32675277 reports G334R as a hypomorphic tetramerization-domain variant with mildly impaired colony suppression and tetramer thermal stability, similar to p.R337H, with variable cancer penetrance in carriers, but no formal VCEP P/LP determination is reported.
PMID:25584008 reports G334R as a maternally inherited germline variant in a pediatric adrenocortical carcinoma case with median TP53 transactivation activity of 86.6% of wild-type, again without a formal VCEP clinical classification.
pm5_candidates.json automated ClinVar same-residue search returned zero usable candidates due to an HTTP 429 rate-limit error, so absence of a qualifying comparator cannot be considered exhaustively confirmed.
Still missing
No same-residue (codon 334) missense variant identified with a confirmed TP53 VCEP Pathogenic or Likely Pathogenic overall clinical classification
Automated pm5_candidates ClinVar same-residue comparator search failed (HTTP 429 Too Many Requests), so the same-residue comparator search is incomplete and should be manually repeated
PP3Not met: Align-GVGD Class C15 falls below the C25-C65 range PP3 requires, despite BayesDel 0.56885.
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Reasoning
Variant NM_000546.6:c.1001G>T / p.(Gly334Val) is missense. The TP53 VCEP's own pre-computed PP3-BP4-codes.xlsx lookup (Supplementary Table S2) lists this exact transcript change with Align-GVGD Class C15 and BayesDel score 0.56885, and assigns 'No evidence' as the preliminary bioinformatic code with a maximum SpliceAI delta of 0 (no splicing-based code change indicated). Per the TP53 VCEP PP3/BP4 flowchart, PP3 requires aGVGD Class C65 (Moderate) or Class C25-C55 (Supporting) together with BayesDel >= 0.16. Although BayesDel (0.56885) exceeds 0.16, the aGVGD class (C15) falls below the C25-C55/C65 bands required for PP3, so the VCEP-specified missense PP3 criterion is not met. The splice-impact sub-path (SpliceAI >= 0.2) also does not apply: case evidence gives SpliceAI max delta score = 0 (pangolin_SG 0.004, pangolin_SL -0.007), far below the 0.2 threshold, and no predicted splice effect is present to invoke the exonic-splice-effect branch of PP3.
Rule
TP53 VCEP v2.4 PP3 (missense): aGVGD Class C65 & BayesDel >=0.16 = Moderate; aGVGD Class C25-C55 & BayesDel >=0.16 = Supporting; not met here per VCEP PP3-BP4-codes.xlsx pre-assignment ('No evidence').
Evidence considered
TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) row for c.1001G>T / p.Gly334Val: Align-GVGD Class C15, BayesDel 0.56885, Preliminary bioinformatic code = 'No evidence', Maximum SpliceAI delta score = 0.
Case-level SpliceAI lookup (spliceai source) reports max delta score = 0.00 (pangolin_SG 0.004, pangolin_SL -0.007) for this variant, consistent with no predicted splicing impact.
TP53 VCEP PP3/BP4/BP7 flowchart (cspec-governed) requires aGVGD Class C65 (PP3_Moderate) or C25-C55 (PP3_Supporting) combined with BayesDel >= 0.16 for missense PP3; this variant's aGVGD class (C15) does not meet either band despite the elevated BayesDel score.
BA1Not met: absent from gnomAD, so no allele frequency reaches the >=0.001 BA1 threshold.
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Reasoning
BA1 is not met. The variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada; therefore no population allele frequency reaches the TP53 VCEP BA1 threshold of filtering allele frequency >=0.001 in a qualifying continental ancestry group.
Rule
TP53 VCEP v2.4 BA1: filtering allele frequency >=0.001 in a qualifying gnomAD continental subpopulation of one ancestry group, with >=2,000 alleles tested and >=2 alleles present; founder-effect groups are excluded.
Evidence considered
The TP53 VCEP version 2.4 specifies BA1 at stand-alone strength when filtering allele frequency is >=0.001 in a single qualifying continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles present.
The variant NM_000546.6:c.1001G>T (p.Gly334Val) is reported as absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0, so there is no observed allele frequency supporting BA1.
Still missing
The case bundle does not provide ancestry-specific allele counts, allele balance, or sample-size details for independent verification of the BA1 threshold; the observed absence nevertheless provides no support for BA1.
BS1Not met: absent from gnomAD, so no allele frequency reaches the >=0.0003 BS1 threshold.
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Reasoning
BS1 is not met. The variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada, with no observed population frequency in a qualifying ancestry group at or above the TP53 VCEP BS1 threshold of 0.0003.
Rule
TP53 VCEP v2.4 BS1: filtering allele frequency >=0.0003 and <0.001 in a qualifying gnomAD continental subpopulation of one ancestry group, with >=2,000 alleles tested and >=2 alleles present; founder-effect groups are excluded.
Evidence considered
The TP53 VCEP version 2.4 specifies BS1 at strong strength when filtering allele frequency is >=0.0003 and <0.001 in a single qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles present; founder-effect groups are excluded.
The variant NM_000546.6:c.1001G>T (p.Gly334Val) is reported as absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0, so no population frequency supports BS1.
Still missing
The case bundle does not provide ancestry-specific allele counts, allele balance, or sample-size details for independent verification of the BS1 threshold; the observed absence nevertheless provides no support for BS1.
BS3Not met: functional assays show loss of function, not the benign profile BS3 requires.
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Reasoning
The TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) pre-assigned functional code for p.G334V is PS3_Moderate, not BS3. Kato et al. class is 'Partially functional' (not Functional), which fails the BS3_Strong requirement ('Functional on Kato et al. data AND no LOF by the majority of available eligible assays') and also fails BS3_Supporting, since the Giacomelli (LOF) and Kawaguchi (Monomer/abnormal) assay results show evidence of loss of function rather than 'no evidence of LOF by all available assays'. The functional evidence for this variant is pathogenic-direction (partial LOF), so BS3 is not met at any strength.
Rule
TP53 VCEP BS3: not met because Kato class is Partially functional (fails BS3_Strong) and Giacomelli/Kawaguchi both show LOF/abnormal function (fails BS3_Supporting's 'no evidence of LOF by all available assays').
Evidence considered
Functional-worksheet.xlsx (Supplementary Table S3) row for G334V: Kato class = Partially functional (not Functional), Giacomelli class = LOF, Kawaguchi class = Monomer (abnormal), Preliminary functional code = PS3_Moderate, which is mutually exclusive with a BS3 assignment.
TP53 VCEP cspec BS3 rule (v2.4) requires 'Functional on Kato et al. data AND no LOF by the majority of available eligible assays' for BS3_Strong, or 'Partially functional on Kato et al. data AND no evidence of LOF by all available assays' for BS3_Supporting; neither condition is met because Kato class is only Partially functional and both Giacomelli and Kawaguchi show LOF/abnormal results.
BP4Not met: BayesDel 0.56885 is far above the <0.16 threshold BP4 requires.
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Reasoning
The TP53 VCEP's PP3-BP4-codes.xlsx (Supplementary Table S2) lookup for this exact variant (c.1001G>T / p.Gly334Val) pre-assigns 'No evidence' rather than a BP4 code. Per the VCEP flowchart, BP4_Moderate requires BayesDel <= -0.008 and BP4_Supporting requires BayesDel < 0.16 and > -0.008 (irrespective of aGVGD except C65), together with no predicted splicing difference (SpliceAI < 0.2). This variant's BayesDel score is 0.56885, well above both BP4 thresholds, so BP4 is not met regardless of the SpliceAI result (max delta = 0, which is consistent with no splicing impact but insufficient alone to trigger BP4 for a missense variant with a high BayesDel score).
Rule
TP53 VCEP v2.4 BP4 (missense): BayesDel <= -0.008 = Moderate; -0.008 < BayesDel < 0.16 = Supporting, AND SpliceAI < 0.2; not met here (BayesDel 0.56885) per VCEP PP3-BP4-codes.xlsx pre-assignment ('No evidence').
BayesDel score 0.56885 exceeds both the BP4_Moderate cutoff (<= -0.008) and the BP4_Supporting range (-0.008 to <0.16) defined in the TP53 VCEP PP3/BP4 flowchart, so the missense BP4 in silico criterion is not met despite SpliceAI predicting no splicing impact (max delta = 0.00).
PS2Not assessed: no de novo observation or parental testing data was available for this variant.
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Reasoning
The TP53 VCEP v2.4 framework applies PS2 exclusively to de novo evidence and requires tallying proband points based on confirmed maternity, confirmed paternity, and the proband's LFS-associated cancer(s). The case-evidence bundle contains no proband phenotype, parental testing, maternity/paternity confirmation, constitutional mosaicism assessment, or de novo observation for NM_000546.6:c.1001G>T (p.Gly334Val), so PS2 cannot be assigned.
Rule
TP53 VCEP v2.4: PS2 uses de novo points based on confirmed maternity, confirmed paternity, and the proband cancer; Supporting = 1 point, Moderate = 2-3 points, Strong = 4-7 points, and Very Strong = >=8 points.
Evidence considered
The TP53 VCEP v2.4 rule states that de novo points are tallied using confirmed maternity and paternity and the type of cancer in the proband, with total points determining PS2 strength.
The consolidated case-evidence bundle identifies the variant as NM_000546.6:c.1001G>T (p.Gly334Val) but contains no proband, parental, or de novo clinical evidence.
Still missing
Proband diagnosis and LFS-associated cancer type/age are not provided.
Parental testing results and confirmation of maternity and paternity are not provided.
No evidence establishes the variant as de novo or as confirmed constitutional mosaicism.
PS4Not assessed: no germline Li-Fraumeni cancer point totals from unrelated probands were available.
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Reasoning
The TP53 VCEP PS4 framework requires Li-Fraumeni syndrome cancer point totals from unrelated probands. No germline proband-level cancer diagnoses, ages, independence assessment, or point total for TP53 c.1001G>T (p.Gly334Val) are provided. Somatic database observations and a single-submitter somatic ClinVar record do not establish the required germline case enrichment.
Rule
ClinGen TP53 VCEP v2.4 PS4: score unrelated germline probands by Li-Fraumeni syndrome-associated cancer points; apply Supporting at 1-1.5 points, Moderate at 2-3.5 points, Strong at 4-7.5 points, and Very Strong at 8 or more points.
Evidence considered
TP53 VCEP v2.4 assigns PS4 by Li-Fraumeni syndrome cancer points: Supporting 1-1.5, Moderate 2-3.5, Strong 4-7.5, and Very Strong at least 8 points.
ClinVar variation 3764945 is a one-star, single-submitter record for a somatic Likely oncogenic assertion and provides no germline proband cancer data or VCEP PS4 point total.
The pre-extracted candidate literature contains no report of the exact variant c.1001G>T or p.Gly334Val suitable for PS4 counting.
Still missing
Independent germline carriers with Li-Fraumeni syndrome-associated cancers, including cancer type and age at diagnosis, are needed to calculate the TP53 VCEP PS4 point total.
A case-control enrichment analysis or adequately ascertained unrelated germline case series for the exact variant is not available.
PM1Not assessed: codon 334 is not on the TP53 VCEP PM1 codon list, and no verified hotspot occurrence count was available.
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Reasoning
Codon 334 is not among the TP53 VCEP PM1 codon list (175, 245, 248, 249, 273, 282). The VCEP alternative pathway allows PM1_Moderate for a germline missense variant seen in cancerhotspots.org with >=10 somatic occurrences of the same amino acid change (Supporting for 2-9). The cancerhotspots.org scrape flagged G334 as a 'statistically significant hotspot' but the extraction was explicitly partial/regex-based with no verified same-amino-acid-change occurrence count, and this scrape result has no corresponding source_registry entry to cite formally. A separate COSMIC lookup recorded 27 somatic occurrences of this exact variant (COSV52759537), but COSMIC is not the VCEP-specified database (cancerhotspots.org) and also lacks a source_registry key, so it cannot be substituted to satisfy this VCEP-specific numeric rule. PMID:12826609 independently documents that Gly-334 sits in a functionally sensitive turn of the p53 tetramerization domain, inactivated by at least three distinct substitutions in yeast transactivation assays, but the TP53 VCEP framework restricts PM1 application strictly to the listed codons or the cancerhotspots.org occurrence-count rule, not general domain-sensitivity reasoning, so this evidence does not independently satisfy PM1 under the governing specification.
Rule
TP53 VCEP PM1 (cspec v2.4): Moderate for codons 175/245/248/249/273/282, or missense variants with >=10 same-amino-acid-change occurrences in cancerhotspots.org (Supporting for 2-9).
Evidence considered
TP53 VCEP cspec PM1 rule: Moderate for the six listed codons (175,245,248,249,273,282) or for missense variants with >=10 same-amino-acid-change occurrences in cancerhotspots.org; Supporting for 2-9 occurrences.
Codon 334 (p.Gly334Val) is not among the six VCEP-listed PM1 codons.
cancerhotspots.org query 'TP53 G334' returned 'This variant lies in a statistically significant hotspot' but the record was noted as regex-extraction-partial with no verified per-amino-acid-change occurrence count, and no source_registry key covers this scrape.
COSMIC record COSV52759537 for this exact variant lists 27 somatic occurrences, but COSMIC is not the VCEP-designated hotspot database and has no source_registry key, so it cannot be used to apply the VCEP PM1 threshold.
PMID:12826609 (Kato et al.) reports Gly-334 as one of 15 tetramerization-domain residues highly susceptible to functional inactivation (inactivated by >=3 distinct substitutions in yeast transactivation assays), supporting general domain sensitivity but not the VCEP's specific PM1 hotspot-count rule.
PP1Not assessed: no family segregation or meiosis count data was available.
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Reasoning
The TP53 VCEP v2.4 PP1 rule requires cosegregation in affected relatives with relevant LFS-associated cancers and counts meioses for individuals who carry the variant and have a relevant cancer, including unaffected obligate carriers. The case-evidence bundle provides no family structure, affected relatives, variant-carrier status in relatives, phenotype details, or meiosis count; therefore PP1 cannot be assessed.
Rule
TP53 VCEP v2.4: Supporting requires cosegregation in 3-4 meioses; Moderate requires 5-6 meioses; Strong requires at least 7 meioses across more than 1 family. Meioses should involve variant carriers with relevant LFS-associated cancer, and may include unaffected obligate carriers.
Evidence considered
The TP53 VCEP v2.4 rule states that meioses are counted for individuals who both carry the variant and have a relevant LFS-associated cancer, with unaffected obligate carriers also eligible for meiosis counting.
The TP53 VCEP v2.4 strength thresholds are Supporting for 3-4 cosegregating meioses, Moderate for 5-6 meioses, and Strong for at least 7 meioses across more than 1 family.
The consolidated case-evidence bundle contains no family segregation or meiosis data for NM_000546.6:c.1001G>T (p.Gly334Val).
Still missing
No family pedigree or list of informative relatives is provided.
No segregation testing results for relatives are provided.
No affected-relative cancer phenotypes or ages are provided.
No count of informative cosegregating meioses is available.
PP4Not assessed: no variant allele fraction or independent observation count was available to assess clonal hematopoiesis.
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Reasoning
For TP53, PP4 is specified for observations of the variant at a low variant allele fraction consistent with clonal hematopoiesis: Supporting for VAF 5-35% and Moderate for at least two independent observations with VAF 5-25%. The available ClinVar record indicates somatic origin but supplies no VAF or independent-observation count, so neither threshold can be assessed.
Rule
ClinGen TP53 VCEP v2.4 PP4: Moderate requires at least two independent observations with VAF 5-25%; Supporting requires one observation with VAF 5-35% or multiple observations with VAF above 25-35% and/or one observation with VAF 5-25%.
Evidence considered
TP53 VCEP v2.4 PP4 requires VAF 5-35% for Supporting evidence or at least two independent observations with VAF 5-25% for Moderate evidence.
ClinVar variation 3764945 lists a somatic submission but contains no VAF and no usable independent-observation details.
Still missing
Variant allele fraction for the exact variant in the relevant specimen(s).
For PP4_Moderate, documentation of at least two independent observations with VAF 5-25%.
BS2Not assessed: no qualifying observations in unaffected women aged 60 or older, or in homozygotes, were available.
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Reasoning
BS2 was not assessed. The case-evidence bundle contains no qualifying observation of this variant in unrelated females aged at least 60 years without cancer from a single source, and no qualifying homozygote evidence.
Rule
TP53 VCEP v2.4 BS2: >=8 qualifying unrelated females aged >=60 years without cancer from a single source for strong, 4-7 for moderate, or 2-3 for supporting; late sarcoma cases are excluded.
Evidence considered
The TP53 VCEP version 2.4 specifies BS2 supporting for 2-3, moderate for 4-7, and strong for >=8 unrelated females aged at least 60 years without cancer, all from one source; the bundle provides no such series.
Still missing
No single-source series of unrelated unaffected females aged >=60 years was provided.
No genotype-level homozygote observations or other unaffected-carrier data were provided.
BS4Not assessed: no family segregation data was available to test for non-segregation.
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Reasoning
The TP53 VCEP v2.4 BS4 rule requires lack of segregation in affected family members diagnosed with LFS-associated cancers. The case-evidence bundle contains no affected-family-member genotypes, phenotypes, pedigree, or non-segregation observations, so BS4 cannot be assessed. No negative segregation evidence should be inferred from the absence of family data.
Rule
TP53 VCEP v2.4: BS4 Strong applies to lack of segregation in affected family members diagnosed with LFS-associated cancers.
Evidence considered
The TP53 VCEP v2.4 rule applies BS4 for lack of segregation in affected family members diagnosed with LFS-associated cancers.
The VCEP cautions that phenocopies and more than one pathogenic variant in a family can mimic lack of segregation.
The consolidated case-evidence bundle contains no affected-relative segregation or non-segregation data for NM_000546.6:c.1001G>T (p.Gly334Val).
Still missing
No affected family members with relevant LFS-associated cancers are documented.
No genotype results for affected relatives are documented.
No validated non-segregation observation is documented.
Potential phenocopies or additional pathogenic variants cannot be evaluated.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: this is a missense change (p.Gly334Val), not a null variant, so the protein-truncation criterion does not apply.
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Reasoning
NM_000546.6:c.1001G>T results in NP_000537.3:p.(Gly334Val), a missense substitution, not a null variant (nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, or exonic/whole-gene deletion). The ClinGen TP53 VCEP CSPEC v2.4 PVS1 decision tree and TP53-specific PVS1 flowchart apply only to null variant classes (nonsense, frameshift, canonical splice, CNV/exon deletion). The case's own pvs1_variant_assessment classifies this variant's consequence_class as 'missense' and variant_bucket as 'other', explicitly stating it does not fall into a generic PVS1 null-variant bucket, and sets apply_generic_pvs1_framework to false with no suggested default strength. No NMD, exon-skipping, or truncation prediction applies to a missense change.
Rule
PVS1 not applicable: variant consequence is missense, not a null (loss-of-function) variant class covered by the TP53 VCEP PVS1 decision tree.
Evidence considered
pvs1_gene_context/pvs1_variant_assessment (case evidence bundle): consequence_class='missense', variant_bucket='other', apply_generic_pvs1_framework=false, rationale states the variant does not fall into nonsense/frameshift/canonical splice PVS1 buckets.
PM3VCEPNot applicable: TP53-related disease is autosomal dominant, so the recessive biallelic-evidence criterion PM3 does not apply.
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Reasoning
The governing ClinGen TP53 Expert Panel specification (Version 2.4) explicitly designates PM3 as not applicable to TP53/Li-Fraumeni syndrome. TP53-associated Li-Fraumeni syndrome is an autosomal dominant disorder, not a recessive disorder for which biallelic phase evidence would support PM3.
VCEP rule
This rule does not apply to TP53/Li-Fraumeni syndrome.
Evidence considered
The TP53 VCEP rule states: this rule does not apply to TP53/Li-Fraumeni syndrome.
The framework identifies Li-Fraumeni syndrome inheritance as autosomal dominant; therefore observations of this variant in trans with another pathogenic variant cannot be used for PM3 under the governing specification.
PM4VCEPNot applicable: this missense change does not alter protein length, the only situation PM4 covers.
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Reasoning
The ClinGen TP53 VCEP CSPEC v2.4 explicitly designates PM4 (protein length change due to in-frame indels/stop-loss) as Not Applicable for TP53. This variant is additionally a missense single-nucleotide substitution (p.Gly334Val) with no change in protein length, so PM4 would not apply on consequence grounds even under a generic framework.
VCEP rule
PM4 marked Not Applicable by TP53 VCEP CSPEC v2.4; variant produces no protein length change in any case.
PP5VCEPNot applicable: the TP53 VCEP designates PP5 not applicable, and no expert-panel germline classification exists for this variant.
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Reasoning
TP53 VCEP v2.4 designates PP5 not applicable. Independently, no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic germline classification is present; the available record is a one-star single-submitter somatic Likely oncogenic assertion and cannot trigger PP5.
VCEP rule
TP53 VCEP v2.4: PP5 is not applicable. Per this review, only an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification could otherwise support PP5.
Evidence considered
The TP53 VCEP specification lists PP5 as Not Applicable.
ClinVar variation 3764945 has no expert-panel submission and its only classified submission is somatic Likely oncogenic, not an expert-panel Pathogenic or Likely pathogenic classification.
BP2VCEPNot applicable: the TP53 VCEP specification designates BP2 as not applicable for this gene.
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Reasoning
The governing ClinGen TP53 Expert Panel specification (Version 2.4) designates BP2 as not applicable. Although the specification describes potential BP2 scenarios involving a phase-confirmed trans observation with a pathogenic or likely pathogenic TP53 variant, or at least three observations with at least two different pathogenic or likely pathogenic TP53 variants when phase is unknown, BP2 is not an applicable criterion for this TP53/Li-Fraumeni syndrome framework.
VCEP rule
Evidence code can be applied in either scenario: the variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or there are three or more observations with a pathogenic or likely pathogenic variant when phase is unknown; in the latter scenario, the variant must be seen with at least two different pathogenic or likely pathogenic TP53 variants. The TP53 VCEP nevertheless designates BP2 as not applicable.
Evidence considered
The TP53 VCEP specification marks BP2 as not applicable while documenting the trans/phase-confirmed and multiple-co-observation scenarios in its instructions.
The supplied case-evidence bundle contains no usable phase-confirmed trans/cis observation, affected-proband co-observation, or inheritance record that would independently alter the VCEP applicability designation.
BP3VCEPNot applicable: this is a missense change, not an in-frame indel, and the TP53 VCEP designates BP3 not applicable.
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Reasoning
The ClinGen TP53 VCEP CSPEC v2.4 explicitly designates BP3 (in-frame indels in a repetitive/non-functional region) as Not Applicable for TP53. This variant is also a missense substitution, not an in-frame indel, and TP53 has no repeat region where BP3 logic would apply.
VCEP rule
BP3 marked Not Applicable by TP53 VCEP CSPEC v2.4; variant is not an in-frame indel in any case.
Variant is a missense substitution, not an in-frame indel, so BP3's repeat-region/non-functional-domain in-frame-indel logic is not relevant regardless of VCEP applicability flag.
BP6VCEPNot applicable: the TP53 VCEP designates BP6 not applicable, and no expert-panel benign classification exists for this variant.
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Reasoning
TP53 VCEP v2.4 designates BP6 not applicable. Independently, no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the available record is a one-star single-submitter somatic Likely oncogenic assertion and cannot trigger BP6.
VCEP rule
TP53 VCEP v2.4: BP6 is not applicable. Per this review, only an exact-variant ClinVar expert-panel Benign or Likely benign classification could otherwise support BP6.
Evidence considered
The TP53 VCEP specification lists BP6 as Not Applicable.
ClinVar variation 3764945 has no expert-panel submission and no Benign or Likely benign classification.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants, and this is a missense change.
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Reasoning
BP7 under the TP53 VCEP specification applies only to synonymous (silent) or intronic variants. NM_000546.6:c.1001G>T is a missense variant (p.(Gly334Val)), so BP7 is not applicable to this variant regardless of its SpliceAI result.
Rule
TP53 VCEP v2.4 BP7 applies only to synonymous/intronic variants; not applicable to this missense variant.
Evidence considered
TP53 VCEP v2.4 BP7 rule is scoped to synonymous/silent and intronic variants only; this variant is a missense substitution (p.Gly334Val), placing it outside BP7's applicability.
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Pangolin splice lossmagnitude shown
-0.007
Pangolin splice gain
0.004
Other predictors
REVEL
0.951
BayesDel
0.569
How the predictions were used
PP3Not met: Align-GVGD Class C15 falls below the C25-C65 range PP3 requires, despite BayesDel 0.56885.
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Reasoning
Variant NM_000546.6:c.1001G>T / p.(Gly334Val) is missense. The TP53 VCEP's own pre-computed PP3-BP4-codes.xlsx lookup (Supplementary Table S2) lists this exact transcript change with Align-GVGD Class C15 and BayesDel score 0.56885, and assigns 'No evidence' as the preliminary bioinformatic code with a maximum SpliceAI delta of 0 (no splicing-based code change indicated). Per the TP53 VCEP PP3/BP4 flowchart, PP3 requires aGVGD Class C65 (Moderate) or Class C25-C55 (Supporting) together with BayesDel >= 0.16. Although BayesDel (0.56885) exceeds 0.16, the aGVGD class (C15) falls below the C25-C55/C65 bands required for PP3, so the VCEP-specified missense PP3 criterion is not met. The splice-impact sub-path (SpliceAI >= 0.2) also does not apply: case evidence gives SpliceAI max delta score = 0 (pangolin_SG 0.004, pangolin_SL -0.007), far below the 0.2 threshold, and no predicted splice effect is present to invoke the exonic-splice-effect branch of PP3.
Rule
TP53 VCEP v2.4 PP3 (missense): aGVGD Class C65 & BayesDel >=0.16 = Moderate; aGVGD Class C25-C55 & BayesDel >=0.16 = Supporting; not met here per VCEP PP3-BP4-codes.xlsx pre-assignment ('No evidence').
Evidence considered
TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) row for c.1001G>T / p.Gly334Val: Align-GVGD Class C15, BayesDel 0.56885, Preliminary bioinformatic code = 'No evidence', Maximum SpliceAI delta score = 0.
Case-level SpliceAI lookup (spliceai source) reports max delta score = 0.00 (pangolin_SG 0.004, pangolin_SL -0.007) for this variant, consistent with no predicted splicing impact.
TP53 VCEP PP3/BP4/BP7 flowchart (cspec-governed) requires aGVGD Class C65 (PP3_Moderate) or C25-C55 (PP3_Supporting) combined with BayesDel >= 0.16 for missense PP3; this variant's aGVGD class (C15) does not meet either band despite the elevated BayesDel score.
BP4Not met: BayesDel 0.56885 is far above the <0.16 threshold BP4 requires.
Details ▾Hide ▴
Reasoning
The TP53 VCEP's PP3-BP4-codes.xlsx (Supplementary Table S2) lookup for this exact variant (c.1001G>T / p.Gly334Val) pre-assigns 'No evidence' rather than a BP4 code. Per the VCEP flowchart, BP4_Moderate requires BayesDel <= -0.008 and BP4_Supporting requires BayesDel < 0.16 and > -0.008 (irrespective of aGVGD except C65), together with no predicted splicing difference (SpliceAI < 0.2). This variant's BayesDel score is 0.56885, well above both BP4 thresholds, so BP4 is not met regardless of the SpliceAI result (max delta = 0, which is consistent with no splicing impact but insufficient alone to trigger BP4 for a missense variant with a high BayesDel score).
Rule
TP53 VCEP v2.4 BP4 (missense): BayesDel <= -0.008 = Moderate; -0.008 < BayesDel < 0.16 = Supporting, AND SpliceAI < 0.2; not met here (BayesDel 0.56885) per VCEP PP3-BP4-codes.xlsx pre-assignment ('No evidence').
BayesDel score 0.56885 exceeds both the BP4_Moderate cutoff (<= -0.008) and the BP4_Supporting range (-0.008 to <0.16) defined in the TP53 VCEP PP3/BP4 flowchart, so the missense BP4 in silico criterion is not met despite SpliceAI predicting no splicing impact (max delta = 0.00).
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants, and this is a missense change.
Details ▾Hide ▴
Reasoning
BP7 under the TP53 VCEP specification applies only to synonymous (silent) or intronic variants. NM_000546.6:c.1001G>T is a missense variant (p.(Gly334Val)), so BP7 is not applicable to this variant regardless of its SpliceAI result.
Rule
TP53 VCEP v2.4 BP7 applies only to synonymous/intronic variants; not applicable to this missense variant.
Evidence considered
TP53 VCEP v2.4 BP7 rule is scoped to synonymous/silent and intronic variants only; this variant is a missense substitution (p.Gly334Val), placing it outside BP7's applicability.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.951. BayesDel score = 0.56885.
7 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
Kato S et al. · 2003 Jul 8
The paper does not explicitly mention TP53 c.1001G>T or p.(Gly334Val). It reports that Gly-334 is one of 15 residues in the p53 tetramerization domain highly sensitive to functional inactivation by amino-acid substitution, being inactivated by at least three distinct substitutions in yeast-based transactivation assays.
These 15 residues are Phe-328, Leu-330, Ile-332, and Arg-333 in the β-strand, Gly-334 in a turn, and Arg-337, Phe-338, Phe-341, Arg-342, Leu-344, Asn-345, Ala-347, Leu-348, Leu-350, and Lys-351 in the α-helix. Leu-330, Ile-332, Gly-334, Arg-337, Phe-341, Leu-344, and Ala-347, especially, were highly susceptible to functional inactivation because they were inactivated by at least three distinct substitutions.
Location Results and Discussion, 'Function-Structure Relationship in the Tetramerization Domain of p53'
Context High-resolution site-directed mutagenesis of 2,314 TP53 missense mutants; yeast-based transactivation assays using EGFP and Ds-Red reporters linked to eight p53-binding sequences.
Mutational processes shape the landscape of TP53 mutations in human cancer.
Giacomelli AO et al. · 2018 Oct
Giacomelli et al. 2018 report a comprehensive TP53 saturation-mutagenesis (MITE) library screened in isogenic TP53-wild-type and TP53-null A549 cells under nutlin-3 and etoposide selection, covering essentially all possible missense and nonsense TP53 alleles. The published text does not report a variant-specific result for p.G334V; the LOF classification (Etoposide Z-score <= -0.21) used for G334V in the VCEP Functional-worksheet.xlsx is drawn from the underlying systematic dataset (Supplementary Tables 2-3), not from prose discussion of this specific variant.
To determine the function of each missense or nonsense TP53 mutation, we created a comprehensive library of TP53 mutants using Mutagenesis by Integrated TilEs (MITE)13–15. We designed the library so that each allele would contain a single mutation and that each of the 20 natural amino acids and a stop codon would be represented at each codon position.
Location Results, paragraph describing the TP53 MITE saturation-mutagenesis library; see also Fig. 2 and Supplementary Tables 2-3
Context Comprehensive TP53 MITE saturation-mutagenesis library screened in isogenic TP53-wild-type and TP53-null A549 cells under p53-activating nutlin-3 or etoposide selection; allele enrichment quantified by massively parallel sequencing.
Other recorded publications
Prevalence and functional consequence of TP53 mutations in pediatric adrenocorti
The exact variant c.1001G>T, p.(Gly334Val) is not mentioned. The paper reports a different substitution at the same codon, G334R, as a maternally inherited germline variant in a child with pediatric adrenocortical carcinoma and no significant family cancer history; median TP53 transactivation activity was 86.6% of wild-type across eight target genes.
A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Canc
This paper does not report TP53 c.1001G>T, p.(Gly334Val). It investigates a different substitution at the same codon, c.1000G>C/A;p.G334R, in the TP53 tetramerization domain, finding mildly impaired colony-suppression activity, mildly reduced tetramer thermal stability, evidence of an altered p53 conformation, and impaired induction of a subset of p53 target genes, while canonical transactivation remained comparable to wild type in some assays. G334R carriers showed variable cancer penetrance including pediatric adrenocortical tumors and later-onset cancers.
Our experimental evidence indicates that TP53 c.1000G>C;p.G334R has a partial defect in p53 function, similar to another hypomorphic TD mutation, p.R337H.
Results, final paragraph before Discussion
Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 3764945)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.951. BayesDel score = 0.56885.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52759537, n = 27 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.5.
The current version is 11.0.07.
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