Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely benign.A likely benign classification under the recorded framework.
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.
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.
Met at Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, with observed allele frequency 0 versus the TP53 VCEP threshold below 0.00003.
Benign criteria applied · 2
BS3Strong
BS3 · strong
Met, strong: the VCEP row assigns BS3 with Kato Functional and majority noLOF among non-Kato assays (2 of 3), subject to splice-effect review.
BP4Moderate
BP4 · moderate
Met at moderate: the TP53 VCEP table pre-assigns BP4_moderate for c.782G>C with BayesDel -0.162486.
Recorded classification: Likely benign
Likely Benign: BS3 (strong) and BP4 (moderate) outweigh PM2 (supporting), producing a TP53 VCEP point score of -5 within the Likely Benign range.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 6 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence/LOF criteria, the variant is an exon 7 missense substitution, p.Ser261Thr, rather than a truncating, canonical splice, or protein-length-altering variant.
The governing TP53 VCEP materials were searched under c.782G>C, p.Ser261Thr, and p.S261T; the PVS1 worksheet had no exact entry, while the VCEP specification marks PM4 and BP3 as not applicable.
The applicable TP53 VCEP version 2.4 was used instead of generic ACMG criteria.
This missense variant is p.Ser261Thr at residue 261. The VCEP hotspot codons and cancerhotspots-specific PM1 requirements do not support PM1, no qualifying same-residue PM5 comparator was identified, and PS1 is not met because neither a qualifying same-amino-acid pathogenic comparator nor the required no-splicing condition is present.
PP2 and BP1 are explicitly not applicable under the TP53 VCEP.
This group evaluated only PP3, BP4, and BP7. The TP53 VCEP framework was used because it governs the case.
The variant is missense, so PP3 and BP4 use one consequence-matched missense path rather than combining REVEL and SpliceAI.
The exact TP53 VCEP Supplementary Table S2 row was found by c.782G>C and p.Ser261Thr; its BP4_moderate assignment was applied directly, while its non-assigned PP3 splice note was not converted into PP3 under the specified path rule.
The single-amino-acid deletion BayesDel file was searched and contained no entry for c.782G>C, p.Ser261Thr, or p.S261T; it is not applicable because this variant is missense.
The TP53 VCEP Version 2.4 governs population evidence for this variant.
Population evidence supports PM2 at Supporting strength because the variant is absent from all-comers and non-cancer gnomAD sources reported for this case.
BA1 and BS1 are not met because no qualifying population frequency reaches either benign threshold; BS2 cannot be assessed without qualifying unaffected older female carriers.
No criteria match.
Met · 3
PM2SupportingMet at Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, with observed allele frequency 0 versus the TP53 VCEP threshold below 0.00003.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 specifies PM2 at Supporting strength when the allele frequency is below 0.00003 in gnomAD or another large sequenced population; if multiple alleles are present in an ancestry group, that group's frequency must remain below 0.00004. The variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer exomes, and gnomAD v3.1 non-cancer genomes, providing an observed allele frequency of 0 in each available source and satisfying PM2_Supporting.
Rule
Apply PM2 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 allele frequency must be <0.00004, excluding founder-effect ancestry groups.
Evidence considered
The TP53 VCEP Version 2.4 requires PM2 at Supporting strength for allele frequency <0.00003; when multiple alleles occur in an ancestry group, that group's frequency must be <0.00004.
GNOMAD_V2_1 reports the variant as absent, corresponding to observed allele frequency 0; GNOMAD_V2_1_NON_CANCER exomes also report it as absent.
GNOMAD_V4_1 reports the variant as absent, corresponding to observed allele frequency 0; GNOMAD_V3_1_NON_CANCER genomes also report it as absent.
BS3StrongMet, strong: the VCEP row assigns BS3 with Kato Functional and majority noLOF among non-Kato assays (2 of 3), subject to splice-effect review.
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Reasoning
The exact TP53 VCEP Functional-worksheet.xlsx entry for p.S261T assigns BS3. It reports Kato Functional, Funk LOF, Giacomelli noLOF, Kotler noLOF, and Kawaguchi NA; among the available non-Kato assays, noLOF is the majority (two of three). This satisfies the TP53 VCEP strong BS3 rule requiring Functional Kato data and no loss of function by the majority of available eligible assays. The VCEP framework also cautions against applying BS3 to a missense variant when PP3 is applied for a predicted splice effect; this variant has SpliceAI max delta 0.638, so the functional assignment is recorded but warrants human review for that interaction.
Rule
Functional on Kato data AND no loss of function by the majority of available eligible assays.
Evidence considered
The exact Functional-worksheet.xlsx entry is S261T: Kato Functional; Funk LOF; Giacomelli noLOF; Kotler noLOF; Kawaguchi NA; preliminary functional code BS3.
The TP53 VCEP BS3 strong rule is Functional on Kato data AND no loss of function by the majority of available eligible assays; the available non-Kato assays are majority noLOF (2 of 3).
The case SpliceAI result has max delta score 0.638, and the TP53 VCEP framework cautions that BS3 should not be applied to missense variants if PP3 is applied based on SpliceAI; this interaction requires human review.
BP4ModerateMet at moderate: the TP53 VCEP table pre-assigns BP4_moderate for c.782G>C with BayesDel -0.162486.
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Reasoning
The variant is a missense substitution. The governing TP53 VCEP Supplementary Table S2 directly pre-assigns BP4_moderate for c.782G>C / p.Ser261Thr (BayesDel class C0; BayesDel score -0.162486), and that pre-assigned VCEP code governs this criterion. The row also reports a maximum SpliceAI delta of 0.64 and flags consideration of PP3 for predicted splicing, but this does not remove the directly assigned BP4_moderate code under the governing-table instruction. REVEL 0.504 is not low enough for generic REVEL BP4 supporting (<=0.29), so no additional generic BP4 evidence is claimed.
Rule
Apply the TP53 VCEP Supplementary Table S2 pre-assigned BP4_moderate code for the exact c.782G>C / p.Ser261Thr row; a governing pre-assignment outranks generic predictor thresholds.
Evidence considered
The governing TP53 VCEP Supplementary Table S2 row for c.782G>C / p.Ser261Thr directly assigns BP4_moderate, with BayesDel class C0 and score -0.162486.
The same authoritative row reports maximum SpliceAI delta 0.64 and the note 'Consider PP3 based on predicted splicing effect'; this note is not a replacement for the explicitly assigned BP4_moderate code.
REVEL is 0.504, which does not meet the supplied generic REVEL BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore the result relies on the VCEP pre-assignment rather than generic REVEL thresholding.
PS1Not met: no qualifying pathogenic p.Ser261Thr comparator is documented, and SpliceAI max delta 0.638 exceeds the VCEP <0.2 no-splicing requirement.
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Reasoning
The TP53 VCEP permits PS1 only when an alternative nucleotide change produces the same amino-acid change and the comparator is classified as pathogenic or likely pathogenic under the VCEP specifications; no qualifying p.Ser261Thr comparator is documented. In addition, the VCEP requires no predicted splicing difference, but this missense variant has a SpliceAI maximum delta of 0.638, exceeding the VCEP no-splicing threshold of <0.2.
Rule
TP53 VCEP v2.4 PS1: same amino-acid change as a VCEP-established pathogenic comparator supports PS1 Strong, or a likely pathogenic comparator supports PS1 Moderate; rule requires no difference using RNA data or SpliceAI <0.2.
Evidence considered
The governing TP53 VCEP version 2.4 states that PS1 compares the same amino-acid change caused by a different nucleotide change and requires the comparator to be pathogenic or likely pathogenic under the TP53 VCEP specifications.
The governing TP53 VCEP version 2.4 requires RNA evidence or SpliceAI <0.2 to exclude a splicing difference before applying PS1.
The case variant is NP_000537.3:p.(Ser261Thr), and SpliceAI reports a maximum delta score of 0.638, with the highest component DS_DL = 0.638.
Still missing
No independently documented alternative nucleotide change causing the same p.Ser261Thr substitution and meeting the TP53 VCEP pathogenic or likely pathogenic requirement.
PS3Not met: Kato classified p.S261T as Functional, while the available non-Kato assays were mostly noLOF (2 noLOF versus 1 LOF).
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Reasoning
The TP53 VCEP Functional-worksheet.xlsx exact p.S261T row assigns BS3, not PS3. The row reports Kato Functional, Funk LOF, Giacomelli noLOF, Kotler noLOF, and Kawaguchi NA. Because PS3 requires non-functional or partially functional Kato results plus concordant loss of function in other eligible assays, the governing PS3 rules are not satisfied. The worksheet's majority result among the available non-Kato assays is noLOF (two noLOF results versus one LOF result), further excluding PS3.
Rule
Non-functional on Kato data AND loss of function by the majority of other eligible assays; supporting pathway requires non-functional Kato AND abnormal Kawaguchi data.
Evidence considered
The exact Functional-worksheet.xlsx entry is S261T: Kato Functional; Funk LOF; Giacomelli noLOF; Kotler noLOF; Kawaguchi NA; preliminary functional code BS3.
The TP53 VCEP PS3 rule requires a non-functional Kato result plus loss of function by the majority of other eligible assays, or the specified Kato/Kawaguchi supporting pathway; neither pathway applies here.
The TP53 VCEP functional flowchart identifies Kato, Funk, Giacomelli, Kotler, and Kawaguchi as eligible functional studies for TP53 missense variants.
PM1Not met: residue 261 is outside the VCEP hotspot codons, cancerhotspots returned no result, and vcep_materials domain_tables is empty.
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Reasoning
The governing TP53 VCEP specifies PM1 Moderate for missense variants at codons 175, 245, 248, 249, 273, or 282, or for germline missense variants with at least 10 cancerhotspots.org somatic occurrences for the same amino-acid change; PM1 Supporting requires 2-9 such cancerhotspots.org occurrences. The variant is at residue 261, the cancerhotspots query returned no result, and the available somatic record is COSMIC with only 3 occurrences, not the specified cancerhotspots.org evidence. The authoritative vcep_materials domain_tables entry is empty, so no additional approved domain list changes this conclusion.
Rule
TP53 VCEP v2.4 PM1: missense at codons 175, 245, 248, 249, 273, or 282 supports Moderate; same-amino-acid cancerhotspots.org occurrences of 2-9 support Supporting and at least 10 support Moderate.
Evidence considered
The governing TP53 VCEP version 2.4 lists PM1 Moderate hotspot codons 175, 245, 248, 249, 273, and 282, and separately allows PM1 for 2-9 or at least 10 same-amino-acid somatic occurrences specifically in cancerhotspots.org.
The variant is p.Ser261Thr at residue 261, which is not one of the six VCEP-listed hotspot codons.
The cancerhotspots source reports no statistically significant hotspot result for TP53 S261.
The authoritative vcep_materials domain_tables object contains no TP53 domain-table entry; therefore no approved critical-domain interval is available from that source.
PM5Not met: the residue-261 review found 0 qualifying pathogenic or likely pathogenic alternate missense comparators for PM5.
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Reasoning
The TP53 VCEP requires a different missense variant at the same residue that is independently classified as pathogenic or likely pathogenic under the VCEP rules, with the likely pathogenic comparator also requiring clinical pathogenicity evidence for PM5 Supporting. The collected same-residue review found zero qualifying comparator variants at residue 261. The available S261A, S261C, S261G, and S261R entries are not documented as qualifying VCEP pathogenic or likely pathogenic comparators, and the case artifact explicitly reports no useful PM5 candidates.
Rule
TP53 VCEP v2.4 PM5: one different VCEP-established pathogenic same-residue missense variant supports Moderate; at least two support Strong; one VCEP-established likely pathogenic comparator with clinical pathogenicity evidence supports Supporting; apply Grantham and exclude predicted splicing with RNA or SpliceAI <0.2.
Evidence considered
The governing TP53 VCEP version 2.4 requires one or more different missense variants at the same amino-acid residue that are pathogenic or likely pathogenic under the VCEP specifications; PM5 Supporting additionally requires clinical pathogenicity evidence for a likely pathogenic comparator.
The residue-261 entries available in the TP53 functional worksheet include S261A, S261C, and S261T, but they do not establish an eligible pathogenic or likely pathogenic comparator for p.Ser261Thr; S261A is assigned BS3_Supporting and S261C is assigned BS3 in the extracted worksheet summary.
The TP53 bioinformatics worksheet lists S261C, S261G, and S261R as BP4 or BP4_moderate entries rather than VCEP pathogenic or likely pathogenic comparator classifications.
The PM5 candidate summary reports five candidates reviewed, zero same-residue candidates, and no useful candidates found.
PP3Not met: missense REVEL 0.504 is below the 0.644 PP3 supporting threshold, and the VCEP row assigns BP4_moderate rather than PP3.
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Reasoning
The variant is a missense substitution, so the applicable PP3/BP4 path is REVEL only. The TP53 VCEP Supplementary Table S2 row for c.782G>C / p.Ser261Thr assigns BP4_moderate and does not assign PP3; the REVEL score is 0.504, below the generic PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The same row notes SpliceAI 0.64 and says to consider PP3 based on predicted splicing, but under the specified consequence-matched path this splice prediction is not used for a missense PP3 determination.
Rule
For a missense variant, evaluate PP3 using REVEL only; the TP53 VCEP row does not pre-assign PP3 for c.782G>C.
Evidence considered
Case normalization identifies NM_000546.5:c.782G>C as the missense variant NP_000537.3:p.(Ser261Thr) / p.(S261T), so the missense REVEL path applies.
The governing TP53 VCEP Supplementary Table S2 row states: c.782G>C, p.Ser261Thr, BayesDel class C0, BayesDel -0.162486, preliminary code BP4_moderate, maximum SpliceAI delta 0.64, and 'Consider PP3 based on predicted splicing effect'.
REVEL is 0.504; the supplied ClinGen SVI calibration defines PP3 supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997), so this score is in the non-supportive gray zone.
The SpliceAI value is not used to assign PP3 because this is a missense variant and the specified rule selects exactly one consequence-matched predictor path.
BA1Not met: the variant is absent from gnomAD v2.1 and v4.1, below the TP53 VCEP BA1 FAF threshold of 0.001.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 specifies BA1 when the filtering allele frequency (FAF) is at least 0.001 in a qualifying continental ancestry group with at least 2,000 alleles tested and at least 2 variant alleles. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying population frequency reaches the BA1 threshold.
Rule
Filtering allele frequency (FAF) of >=0.001 in a gnomAD continental subpopulation of a single genetic ancestry group, excluding founder-effect groups; the group must have >=2,000 alleles tested and at least 2 alleles present.
Evidence considered
The TP53 VCEP Version 2.4 defines BA1 as FAF >=0.001 in a qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
GNOMAD_V2_1 reports the variant as absent; GNOMAD_V2_1_NON_CANCER also reports it as absent.
GNOMAD_V4_1 reports the variant as absent; GNOMAD_V3_1_NON_CANCER also reports it as absent.
BS1Not met: the variant is absent from gnomAD v2.1 and v4.1, below the TP53 VCEP BS1 FAF range beginning at 0.0003.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 specifies BS1 when the filtering allele frequency is at least 0.0003 but below 0.001 in a qualifying continental ancestry group with at least 2,000 alleles tested and at least 2 variant alleles. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying population frequency reaches the BS1 threshold.
Rule
Filtering allele frequency (FAF) of >=0.0003 but <0.001 in a gnomAD continental subpopulation of a single genetic ancestry group, excluding founder-effect groups; the group must have >=2,000 alleles tested and at least 2 alleles present.
Evidence considered
The TP53 VCEP Version 2.4 defines BS1 as FAF >=0.0003 and <0.001 in a qualifying continental ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
GNOMAD_V2_1 reports the variant as absent; GNOMAD_V2_1_NON_CANCER also reports it as absent.
GNOMAD_V4_1 reports the variant as absent; GNOMAD_V3_1_NON_CANCER also reports it as absent.
PS2Not assessed: no qualifying de novo proband, parental confirmation, or PS2 point total is available for NM_000546.5:c.782G>C.
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Reasoning
The TP53 VCEP specifies that de novo evidence is evaluated exclusively with PS2, because PM6 is not used, and requires tallying de novo points from proband LFS-associated cancer type plus confirmed maternity and paternity. The case materials provide no proband cancer diagnosis, age, parental testing, maternity/paternity confirmation, constitutional mosaicism assessment, or qualifying de novo observation for NM_000546.5:c.782G>C (p.Ser261Thr). The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.782G>C, p.Ser261Thr, and p.S261T; it contains the cancer categories and PS2 thresholds but no variant-specific entry. Therefore PS2 cannot be assigned a strength from the available evidence.
Rule
TP53 VCEP PS2: tally de novo points using qualifying LFS-associated proband cancers and confirmed maternity and paternity; Supporting = 1 point, Moderate = 2-3 points, Strong = 4-7 points, Very Strong = >=8 points. PM6 is not used by this VCEP.
Evidence considered
The TP53 VCEP Version 2.4 PS2 rule states that PS2 is the exclusive de novo code, with PM6 dropped, and assigns Supporting for 1 point, Moderate for 2-3 points, Strong for 4-7 points, and Very Strong for at least 8 points.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf lists the qualifying LFS cancer categories, maternity/paternity-dependent point values, and PS2 thresholds, but no row keyed to c.782G>C, p.Ser261Thr, or p.S261T was found.
Still missing
No documented proband LFS-associated cancer type or age at diagnosis.
No parental genotyping or confirmed maternity and paternity.
No documented de novo observation or constitutional mosaicism assessment.
No variant-specific entry was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf after searching c.782G>C, p.Ser261Thr, and p.S261T.
PS4Not assessed: no proband phenotype or cancer-history data are available to assign TP53 PS4 points against the 1-1.5, 2-3.5, 4-7.5, or >=8 thresholds.
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Reasoning
The TP53 VCEP specifies PS4 using proband points: 0.5 for Revised Chompret criteria, 1 for Classic LFS criteria, and 0.5 for an unrelated proband with HER2-positive breast cancer diagnosed before age 40; its strength thresholds are Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, and Very Strong >=8 points. The case materials provide no proband phenotype, cancer diagnosis or age, family-history assessment, HER2 status, de novo status, case-control odds ratio, or other variant-specific clinical observations from which PS4 points can be assigned. The ClinVar record is an exact-variant match but contains only uncertain-significance laboratory submissions and no expert-panel classification. The governing PS4-Points-Table.pdf was searched for c.782G>C, p.Ser261Thr, and p.S261T; no variant-specific entry was found, so this is a gap in that file rather than evidence that PS4 evidence is absent.
The TP53 VCEP Version 2.4 framework states that PS4 is applicable and assigns 0.5 point for Revised Chompret criteria, 1 point for Classic LFS criteria, and 0.5 point for an unrelated proband with HER2-positive breast cancer diagnosed before age 40.
The same framework defines PS4 strength thresholds as Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, and Very Strong >=8 points.
The exact-variant ClinVar record NM_000546.6(TP53):c.782G>C (p.Ser261Thr) is classified as uncertain significance with criteria-provided laboratory submissions and zero expert-panel submissions; this is not usable PS4 clinical enrichment evidence.
The governing PS4-Points-Table.pdf.txt was searched for c.782G>C, p.Ser261Thr, and p.S261T and contained no variant-specific row.
Still missing
No proband cancer diagnoses, ages at diagnosis, family history, Classic LFS or Revised Chompret assessment, or HER2 status were supplied.
No variant-specific case-control enrichment estimate or confidence interval was supplied.
No entry for c.782G>C, p.Ser261Thr, or p.S261T was found when PS4-Points-Table.pdf.txt was searched.
PP1Not assessed: no variant-positive affected relatives, obligate carriers, or countable PP1 meioses are documented for this variant.
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Reasoning
The TP53 VCEP requires PP1 meioses to be counted only for individuals who both carry the variant and have a relevant LFS-associated cancer, with unaffected obligate carriers permitted; Supporting requires 3-4 meioses, Moderate 5-6, and Strong at least 7 meioses across more than one family. The case materials contain no affected relatives, variant-positive relatives, unaffected obligate carriers, family structure, phase information, or segregation observations for NM_000546.5:c.782G>C (p.Ser261Thr). The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.782G>C, p.Ser261Thr, and p.S261T; it provides the relevant cancer definitions and thresholds but no variant-specific entry. Therefore PP1 cannot be assigned.
Rule
TP53 VCEP PP1: count meioses involving variant-positive individuals with relevant LFS-associated cancers or unaffected obligate carriers; Supporting = 3-4 meioses, Moderate = 5-6, Strong = >=7 meioses across >1 family.
Evidence considered
The TP53 VCEP PP1 rule counts meioses for variant-positive individuals with relevant LFS-associated cancers, permits unaffected obligate carriers, and assigns Supporting for 3-4 meioses, Moderate for 5-6, and Strong for at least 7 meioses across more than one family.
The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf defines relevant LFS-associated cancers, but no row keyed to c.782G>C, p.Ser261Thr, or p.S261T was found.
Still missing
No family pedigree or list of affected relatives.
No germline testing results for relatives or unaffected obligate carriers.
No qualifying segregation observations or meiosis count.
No variant-specific entry was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf after searching c.782G>C, p.Ser261Thr, and p.S261T.
PP4Not assessed: no multigene-panel VAF observation is available to compare with the TP53 PP4 Supporting 5-35% or Moderate 5-25% ranges.
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Reasoning
The TP53 VCEP uses PP4 for low-variant-allele-fraction TP53 variants detected on multigene panel testing, with Supporting strength for one or more observations at VAF 5-35% and Moderate strength for at least two independent observations at VAF 5-25%; the rule cannot be combined with phenotype-based PS4, PS2, or PP1 in the same individual and requires a non-blood-cancer multigene-panel context. The available case evidence reports no VAF observation, test context, number of observations, blood-cancer status, or phenotype-based exclusion. Therefore PP4 cannot be assessed from the supplied evidence.
Rule
Supporting = one or more multigene-panel observations with VAF 5-35%; Moderate = at least two independent observations with VAF 5-25%, subject to VCEP caveats.
Evidence considered
The TP53 VCEP PP4 rule requires multigene-panel detection and assigns Supporting strength to an observation at VAF 5-35% and Moderate strength to at least two independent observations at VAF 5-25%.
The VCEP states that PP4 should not be applied in a patient with blood cancer and cannot be combined in the same individual with phenotype-based PS4, PS2, or PP1.
The case materials contain no VAF, multigene-panel context, observation count, or blood-cancer status for this variant.
Still missing
No multigene-panel detection context or variant allele fraction was supplied.
No number of independent VAF observations was supplied.
No blood-cancer status or information permitting the VCEP PP4 caveat assessment was supplied.
BS2Not assessed: no qualifying unaffected females aged 60 years or older carrying the variant were reported for the TP53 VCEP BS2 threshold of at least 2.
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Reasoning
The TP53 VCEP Version 2.4 requires at least 2 unrelated females aged 60 years or older without cancer for BS2_Supporting, with higher strengths requiring 4-7 or at least 8 such individuals from one source. The available population data report the variant as absent but provide no qualifying unaffected older female carriers or homozygote observations, so BS2 cannot be assessed.
Rule
At least 2 unrelated females aged >=60 years without cancer from a single source for BS2_Supporting; 4-7 for BS2_Moderate; at least 8 for BS2_Strong. Individuals with sarcoma diagnosed at age >=61 years are excluded.
Evidence considered
The TP53 VCEP Version 2.4 defines BS2_Supporting as 2-3 unrelated females aged at least 60 years without cancer from a single source; 4-7 supports BS2_Moderate and at least 8 supports BS2_Strong.
GNOMAD_V2_1 and GNOMAD_V4_1 report the variant as absent and do not provide qualifying unaffected older female carrier observations or homozygote data.
Still missing
A single-source cohort or database report of qualifying unrelated female carriers aged >=60 years without cancer is unavailable.
Homozygote observations and relevant penetrance information are unavailable.
BS4Not assessed: no affected non-carrier relatives or other documented lack-of-segregation evidence is available.
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Reasoning
The TP53 VCEP permits BS4 at Strong strength for lack of segregation in affected family members with LFS-associated cancers, while cautioning that phenocopies and more than one pathogenic variant can confound apparent non-segregation. The case materials contain no affected family members, family genotypes, non-carrier affected relatives, pedigree, or other documented lack-of-segregation observation for NM_000546.5:c.782G>C (p.Ser261Thr). Consequently, BS4 cannot be assessed.
Rule
TP53 VCEP BS4: Strong for lack of segregation in affected family members with LFS-associated cancers, with consideration of phenocopies and alternative pathogenic variants.
Evidence considered
The TP53 VCEP BS4 rule applies Strong evidence for lack of segregation in affected family members diagnosed with LFS-associated cancers and cautions that phenocopies or another pathogenic variant may confound the finding.
Still missing
No pedigree or affected-family-member information.
No genotype results demonstrating lack of segregation.
No assessment of phenocopy or alternative pathogenic-variant confounding.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.782G>C is an exon 7 missense variant producing p.Ser261Thr, not a VCEP-defined null or canonical splice variant for PVS1.
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Reasoning
PVS1 is not applicable. NM_000546.5:c.782G>C is an exonic missense substitution in exon 7, producing NP_000537.3:p.(Ser261Thr) (p.S261T), not a nonsense, frameshift, canonical splice-site, or other null variant. The TP53 VCEP PVS1 flowchart governs null and canonical splice variants; its worksheet has no entry for c.782G>C, p.Ser261Thr, or p.S261T. Although SpliceAI reports a donor-loss delta of 0.638, this does not convert the missense substitution into a PVS1-eligible canonical splice variant, and no VCEP pre-assigned PVS1 strength applies.
Rule
TP53 VCEP PVS1 flowchart and splicing worksheet; PVS1 applies to defined null or canonical splice variants, not ordinary missense substitutions.
Evidence considered
Variant normalization identifies NM_000546.5:c.782G>C as NP_000537.3:p.(Ser261Thr), an exonic missense substitution located in exon 7.
The TP53 VCEP PVS1 flowchart applies PVS1 to null variants and canonical GT-AG splice-site variants, with strength determined by NMD and the affected protein region; it does not define a PVS1 assignment for this missense substitution.
The PVS1 splicing worksheet was searched for c.782G>C, p.Ser261Thr, and p.S261T; no exact variant entry was found.
SpliceAI maximum delta is 0.638, specifically donor loss 0.638, but this exonic splice-impact prediction does not establish a VCEP pre-assigned PVS1 call for the missense variant.
Still missing
No entry for c.782G>C, p.Ser261Thr, or p.S261T was found in PVS1-Flowchart.pdf.txt or PVS1-Splicing-Worksheet.xlsx.txt.
PM3VCEPNot applicable: the TP53 VCEP version 2.4 explicitly designates PM3 as not applicable.
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Reasoning
The governing ClinGen TP53 Expert Panel Specifications, version 2.4, explicitly designate PM3 as not applicable for TP53. Accordingly, phase, affected-proband observations, and the presence or absence of pathogenic variants in trans cannot be used to apply PM3 in this framework, despite the documented autosomal-dominant Li-Fraumeni syndrome context.
VCEP rule
PM3: Not Applicable
Evidence considered
The governing TP53 VCEP framework is the ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines, version 2.4.
That specification explicitly lists PM3 applicability as Not Applicable; therefore no phase or trans-observation evidence can activate PM3 under this framework.
PM4VCEPNot applicable: p.Ser261Thr is a single-amino-acid substitution with no protein-length change, whereas PM4 concerns qualifying length-altering variants.
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Reasoning
PM4 is not applicable. The variant is a single-nucleotide missense substitution producing p.Ser261Thr, with no deletion, insertion, repeat expansion, or other protein-length change. The TP53 VCEP specification explicitly lists PM4 as not applicable.
VCEP rule
TP53 VCEP PM4 applicability: not applicable; this missense substitution does not alter protein length.
Evidence considered
Variant normalization shows a G>C single-nucleotide substitution causing the amino-acid change p.Ser261Thr, without an altered protein length.
The TP53 VCEP specification marks PM4 as not applicable.
PM6VCEPNot applicable: the TP53 VCEP dropped PM6 and directs all de novo evidence to PS2.
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Reasoning
PM6 is not applicable under the TP53 VCEP Version 2.4 framework. The VCEP explicitly states that PM6 is dropped and PS2 is used exclusively for de novo evidence, including cases where maternity and paternity are not confirmed.
VCEP rule
TP53 VCEP PM6: not applicable; the VCEP dropped PM6 and uses PS2 exclusively for de novo evidence.
Evidence considered
The TP53 VCEP Version 2.4 PM6 specification marks PM6 as not applicable and directs users to the combined PS2 de novo rule.
PP2VCEPNot applicable: the TP53 VCEP explicitly designates PP2 as not applicable for this gene.
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Reasoning
The governing TP53 VCEP marks PP2 as not applicable because TP53 is not interpreted using the generic PP2 rule for a low rate of benign missense variation and a missense disease mechanism.
VCEP rule
TP53 VCEP v2.4 PP2: not applicable.
Evidence considered
The governing TP53 VCEP version 2.4 marks PP2 as Not applicable.
PP5VCEPNot applicable: the TP53 VCEP prohibits PP5, and ClinVar has zero exact-variant expert-panel submissions supporting Pathogenic or Likely pathogenic.
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Reasoning
The TP53 VCEP Version 2.4 explicitly marks PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact-variant ClinVar record also has zero expert-panel submissions and only uncertain-significance laboratory submissions, so PP5 cannot be triggered under the requested exact-variant expert-panel rule.
VCEP rule
Not applicable for this TP53 VCEP; otherwise exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification would be required.
Evidence considered
The TP53 VCEP explicitly states that PP5 is not applicable and is not for use.
ClinVar reports the exact variant as uncertain significance with zero expert-panel submissions; ordinary laboratory submissions do not satisfy the required expert-panel condition.
BP1VCEPNot applicable: the TP53 VCEP explicitly excludes BP1 because truncating variants are not the primary disease mechanism.
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Reasoning
The governing TP53 VCEP marks BP1 as not applicable because truncating variants account for only a portion of TP53 disease-causing variation; the generic benign rule for a gene in which disease is primarily caused by truncating variants therefore cannot be used.
VCEP rule
TP53 VCEP v2.4 BP1: not applicable; truncating variants account for only a portion of disease-causing variants.
Evidence considered
The governing TP53 VCEP version 2.4 marks BP1 as Not applicable and states that truncating variants account for only a portion of disease-causing TP53 variants.
BP2VCEPNot applicable: the TP53 VCEP version 2.4 explicitly designates BP2 as not applicable.
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Reasoning
The governing ClinGen TP53 Expert Panel Specifications, version 2.4, explicitly designate BP2 as not applicable for TP53. Therefore, evidence concerning a pathogenic variant in cis or the absence of a pathogenic variant in trans is not assessed under BP2 for this variant.
VCEP rule
BP2: Not Applicable
Evidence considered
The governing TP53 VCEP framework is the ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines, version 2.4.
That specification explicitly lists BP2 applicability as Not Applicable; phase and cis/trans allelic observations therefore do not support BP2 in this framework.
BP3VCEPNot applicable: p.Ser261Thr is a missense substitution, not an in-frame insertion or deletion in a repetitive region lacking known function.
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Reasoning
BP3 is not applicable. BP3 is reserved for in-frame deletions or insertions in a repetitive region without a known function. NM_000546.5:c.782G>C is a missense substitution producing p.Ser261Thr, not an in-frame deletion or insertion, and the TP53 VCEP specification marks BP3 as not applicable.
VCEP rule
TP53 VCEP BP3 applicability: not applicable; the variant is not an in-frame insertion or deletion.
Evidence considered
Variant normalization identifies NM_000546.5:c.782G>C as the missense change NP_000537.3:p.(Ser261Thr), not an in-frame insertion or deletion.
The TP53 VCEP BP3 rule is explicitly not applicable and is limited to in-frame deletions or insertions in repetitive regions without known function.
BP5VCEPNot applicable: the TP53 VCEP marks BP5 as not applicable, regardless of the available uncertain-significance ClinVar record.
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Reasoning
The TP53 VCEP Version 2.4 explicitly marks BP5 as not applicable. No alternate molecular basis is therefore assessed under this VCEP criterion. The available ClinVar record is uncertain significance and does not provide a governing VCEP BP5 assignment.
VCEP rule
Not applicable for this TP53 VCEP.
Evidence considered
The TP53 VCEP explicitly marks BP5 as not applicable.
ClinVar reports uncertain significance for the exact variant and provides no VCEP BP5 assignment.
BP6VCEPNot applicable: the TP53 VCEP prohibits BP6, and ClinVar has zero exact-variant expert-panel submissions supporting Benign or Likely benign.
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Reasoning
The TP53 VCEP Version 2.4 explicitly marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact-variant ClinVar record has zero expert-panel submissions and no Benign or Likely benign expert-panel classification; its ordinary laboratory uncertain-significance submissions cannot trigger BP6 under the requested rule.
VCEP rule
Not applicable for this TP53 VCEP; otherwise exact-variant ClinVar expert-panel Benign or Likely benign classification would be required.
Evidence considered
The TP53 VCEP explicitly states that BP6 is not applicable and is not for use.
ClinVar reports the exact variant as uncertain significance with zero expert-panel submissions; ordinary laboratory submissions do not satisfy the required expert-panel condition.
BP7N/ANot applicable: c.782G>C is missense p.Ser261Thr, not a synonymous variant required for BP7.
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Reasoning
BP7 applies only to synonymous variants. NM_000546.5:c.782G>C produces the missense substitution p.(Ser261Thr), so BP7 is outside its criterion scope and is not evaluated.
Rule
BP7 applies only to synonymous variants; do not evaluate BP7 for a missense variant.
Evidence considered
Variant normalization identifies c.782G>C as the missense protein change p.(Ser261Thr) / p.(S261T).
The TP53 VCEP BP7 framework limits BP7 to synonymous (silent) or qualifying intronic variants; this missense variant is out of scope.
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.
TP53NM_000546.5
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
SpliceAI acceptor lossat -341 bp
0.066
SpliceAI acceptor gainat +6 bp
0.000
SpliceAI donor lossat +0 bp
0.638
SpliceAI donor gainat -290 bp
0.013
Pangolin splice lossmagnitude shown
-0.846
Pangolin splice gain
0.010
Other predictors
REVEL
0.504
BayesDel
-0.162
How the predictions were used
BP4ModerateMet at moderate: the TP53 VCEP table pre-assigns BP4_moderate for c.782G>C with BayesDel -0.162486.
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Reasoning
The variant is a missense substitution. The governing TP53 VCEP Supplementary Table S2 directly pre-assigns BP4_moderate for c.782G>C / p.Ser261Thr (BayesDel class C0; BayesDel score -0.162486), and that pre-assigned VCEP code governs this criterion. The row also reports a maximum SpliceAI delta of 0.64 and flags consideration of PP3 for predicted splicing, but this does not remove the directly assigned BP4_moderate code under the governing-table instruction. REVEL 0.504 is not low enough for generic REVEL BP4 supporting (<=0.29), so no additional generic BP4 evidence is claimed.
Rule
Apply the TP53 VCEP Supplementary Table S2 pre-assigned BP4_moderate code for the exact c.782G>C / p.Ser261Thr row; a governing pre-assignment outranks generic predictor thresholds.
Evidence considered
The governing TP53 VCEP Supplementary Table S2 row for c.782G>C / p.Ser261Thr directly assigns BP4_moderate, with BayesDel class C0 and score -0.162486.
The same authoritative row reports maximum SpliceAI delta 0.64 and the note 'Consider PP3 based on predicted splicing effect'; this note is not a replacement for the explicitly assigned BP4_moderate code.
REVEL is 0.504, which does not meet the supplied generic REVEL BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore the result relies on the VCEP pre-assignment rather than generic REVEL thresholding.
PP3Not met: missense REVEL 0.504 is below the 0.644 PP3 supporting threshold, and the VCEP row assigns BP4_moderate rather than PP3.
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Reasoning
The variant is a missense substitution, so the applicable PP3/BP4 path is REVEL only. The TP53 VCEP Supplementary Table S2 row for c.782G>C / p.Ser261Thr assigns BP4_moderate and does not assign PP3; the REVEL score is 0.504, below the generic PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The same row notes SpliceAI 0.64 and says to consider PP3 based on predicted splicing, but under the specified consequence-matched path this splice prediction is not used for a missense PP3 determination.
Rule
For a missense variant, evaluate PP3 using REVEL only; the TP53 VCEP row does not pre-assign PP3 for c.782G>C.
Evidence considered
Case normalization identifies NM_000546.5:c.782G>C as the missense variant NP_000537.3:p.(Ser261Thr) / p.(S261T), so the missense REVEL path applies.
The governing TP53 VCEP Supplementary Table S2 row states: c.782G>C, p.Ser261Thr, BayesDel class C0, BayesDel -0.162486, preliminary code BP4_moderate, maximum SpliceAI delta 0.64, and 'Consider PP3 based on predicted splicing effect'.
REVEL is 0.504; the supplied ClinGen SVI calibration defines PP3 supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997), so this score is in the non-supportive gray zone.
The SpliceAI value is not used to assign PP3 because this is a missense variant and the specified rule selects exactly one consequence-matched predictor path.
BP7N/ANot applicable: c.782G>C is missense p.Ser261Thr, not a synonymous variant required for BP7.
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Reasoning
BP7 applies only to synonymous variants. NM_000546.5:c.782G>C produces the missense substitution p.(Ser261Thr), so BP7 is outside its criterion scope and is not evaluated.
Rule
BP7 applies only to synonymous variants; do not evaluate BP7 for a missense variant.
Evidence considered
Variant normalization identifies c.782G>C as the missense protein change p.(Ser261Thr) / p.(S261T).
The TP53 VCEP BP7 framework limits BP7 to synonymous (silent) or qualifying intronic variants; this missense variant is out of scope.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.64). REVEL score = 0.504. BayesDel score = -0.162486.
8 paper records listed. 1 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
Kato et al. report a systematic yeast-based functional analysis of 2,314 TP53 missense mutants using sequence-specific transactivation assays across eight p53-responsive promoters. The paper provides the assay methodology underlying the VCEP worksheet's Kato functional classification, but does not explicitly mention TP53 c.782G>C or p.Ser261Thr.
The resulting mutation library consists of 2,314 yeast clones containing distinct TP53 cDNAs with point mutations covering all possible amino acid substitutions caused by single-nucleotide substitutions throughout the full length of the TP53 ORF, except for the translation initiation ATG codon.
Location Results, ‘Construction of 2,314 Distinct p53 Missense Mutations’; Results, ‘Evaluation of 2,314 Missense Mutations on Sequence-Specific Transactivation’
Context Comprehensive site-directed TP53 missense-mutant library evaluated using yeast-based p53 transactivation assays with EGFP and Ds-Red reporters driven by eight p53-binding sequences; selected mutants were also tested with luciferase reporters in Saos-2 human osteosarcoma cells.
Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigen
The paper describes the TP53 core DNA-binding domain as spanning residues 102-292 and reports that many tumor-associated mutations in this domain impair sequence-specific DNA binding. It does not mention p.Ser261Thr or provide variant-specific evidence. This general structural context was not used to override the TP53 VCEP's specified PM1 codons or the absence of an authoritative domain-table entry.
The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292), and they result in loss of DNA binding.
Abstract; Introduction, paragraph discussing the p53 core domain
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
Saslow D et al. · 2007
This paper does not mention TP53 c.782G>C or NP_000537.3:p.(S261T); it discusses general breast-cancer screening guidance for TP53-associated Li-Fraumeni syndrome and provides no variant-specific phenotype or case-control evidence.
A high risk of breast cancer also occurs with mutations in the TP53 gene (Li-Fraumeni syndrome) and the PTEN gene (Cowden and Bannayan-Riley-Ruvalcaba syndromes).
Background, Clinical Indicators of Risk; Table 1
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.
Buratti E et al. · 2007
This paper does not explicitly mention TP53 or the specific variant c.782G>C / NP_000537.3:p.(S261T); it describes a literature compilation and computational analysis of mutation-induced aberrant splice sites without variant-specific clinical evidence.
An exhaustive search for previously published aberrant 5′ss identified 305 unique aberrant 5′ss in 166 genes (Table 1).
Results, Mutations that activate aberrant 5′ss, first paragraph
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
Lu KH et al. · 2014
This paper does not mention TP53 c.782G>C or NP_000537.3:p.(S261T); it identifies TP53-associated cancer risks and Li-Fraumeni syndrome counseling considerations without variant-specific clinical observations.
Table 2, Cancers for Which Genetic Counseling and Testing Should Be Considered, Even in Absence of Family History
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
Hampel H et al. · 2015
This paper does not report TP53 c.782G>C or NP_000537.3:p.(S261T); it describes referral criteria for cancer predisposition assessment, including Li-Fraumeni syndrome, without variant-specific phenotype or segregation data.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 187005)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.64). REVEL score = 0.504. BayesDel score = -0.162486.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52929094, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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