0%
TP53c.877G>ALikely benign
Print report
Variant interpretation report

TP53 c.877G>A, p.(Gly293Arg)

NM_000546.6:c.877G>A NP_000537.3:p.(Gly293Arg) Missense · exon 8 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stress such as DNA damage by switching on genes that trigger cell cycle arrest, DNA repair, senescence, or programmed cell death. In healthy cells, p53 is kept at low levels by constant degradation, but stress signals stabilize and activate it to protect against damaged cells surviving and dividing. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a condition marked by a high risk of developing multiple cancers at a young age. TP53 is the most commonly mutated gene across human cancers, and loss of its normal function promotes tumor growth, spread, drug resistance, and genomic instability.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen TP53 VCEP v2.4. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v2.1 non-cancer exome AF was 8.44067e-06, below the TP53 PM2 threshold of 0.00003, with no homozygotes.

Benign criteria applied · 2
BS3Strong
BS3 · strong

Met, strong: TP53 VCEP assigns BS3 because Kato is functional and both available additional assays, Funk and Giacomelli, are noLOF.

BP4Moderate
BP4 · moderate

Met at moderate strength: the exact TP53 lookup assigns BP4_moderate with BayesDel -0.0095438 and class C0.

Recorded classification: Likely benign

Likely Benign: PM2 supporting (+1), BS3 strong (-4), and BP4 moderate (-2) produce -5 points under the TP53 Version 2.4 framework.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,614,170 alleles

gnomAD v4.1: 3 / 1,614,170 alleles. Recorded AF 1.85854e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95286e-06; MAF= 0.00080%, 2/251482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

Recorded REVEL score: 0.402. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
6 reported laboratory submissions

4 Uncertain significance · 1 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

Applied · BS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
6 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52752246, n = 6 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 7 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

For this missense p.Gly293Arg variant, the TP53-specific framework controls: PM1 is not met because residue 293 is outside the specified critical codons and no qualifying hotspot was found; PS1 and PM5 remain unassessed because qualifying comparator evidence is incomplete.

PP2 and BP1 are not applicable under the governing TP53 VCEP.

No PS2, PP1, or BS4 evidence can be assigned because the case contains no variant-specific proband, parental, family segregation, or non-segregation observations.

PM6 is not applicable under the governing TP53 framework.

For NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R), the governing TP53 Functional-worksheet.xlsx pre-assignment is BS3, with Kato Functional and Funk/Giacomelli noLOF; no PS3 pathway is satisfied.

Population evidence supports PM2 at Supporting strength only; BA1 and BS1 are not met because the observed frequencies are below their TP53 VCEP thresholds, and BS2 is not assessable without qualifying individual-level observations.

Met · 3

PM2 SupportingMet at supporting: gnomAD v2.1 non-cancer exome AF was 8.44067e-06, below the TP53 PM2 threshold of 0.00003, with no homozygotes. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires PM2 at Supporting strength when total allele frequency is below 0.00003, and when multiple alleles occur in an ancestry group that group's frequency must remain below 0.00004. Using the specified gnomAD v2.1 non-cancer exome subset, the variant has AF 8.440670526866655e-06 (2/236,948 alleles), no homozygotes, and the highest ancestry AF is South Asian 3.2758959575443885e-05 (1/30,526); no ancestry group has multiple observed variant alleles. gnomAD v4.1 independently reports total AF 1.85854e-06 and zero homozygotes.

Rule
TP53 VCEP PM2: apply at Supporting strength when AF <0.00003; if multiple alleles occur in an ancestry group, that group's AF must be <0.00004; ignore founder-effect groups.
Evidence considered
  • The TP53 Expert Panel specification applies PM2 at Supporting strength for AF <0.00003; if an ancestry group contains multiple variant alleles, its AF must be <0.00004, with founder-effect groups ignored.
  • The specified gnomAD v2.1 non-cancer exome subset reports AF 8.440670526866655e-06 from 2/236,948 alleles, zero homozygotes, and South Asian AF 3.2758959575443885e-05 from 1/30,526 alleles; no ancestry group has multiple observed variant alleles.
  • gnomAD v4.1 reports total AF 1.8585403024464585e-06 from 3/1,614,170 alleles and zero homozygotes, consistent with rarity.
Sources
final_classification_frameworkgnomad_v2 ↗gnomad_v4 ↗
BS3 StrongMet, strong: TP53 VCEP assigns BS3 because Kato is functional and both available additional assays, Funk and Giacomelli, are noLOF. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP Functional-worksheet.xlsx pre-assigns BS3 for p.G293R (NM_000546.6:c.877G>A; p.Gly293Arg). The row records Functional Kato data, noLOF Funk data, noLOF Giacomelli data, and NA for Kotler and Kawaguchi. This matches the TP53 BS3_Strong rule: functional on Kato data and no loss of function by the majority of available eligible assays. The worksheet's pre-assigned VCEP code outranks generic thresholds. The Flowchart-for-application-of-functional-rule-codes.pdf was searched under c.877G>A, p.Gly293Arg, and p.G293R and has no separate variant-specific entry. The extracted Kato paper does not explicitly mention G293R, so the BS3 determination rests on the governing VCEP worksheet rather than an independent paper-level variant result.

Rule
TP53 VCEP BS3: Strong = functional on Kato et al. data AND no loss of function by the majority of available eligible assays; Supporting = partially functional Kato AND no LOF by all available assays.
Evidence considered
  • Functional-worksheet.xlsx directly lists G293R as: Kato Functional; Funk noLOF; Giacomelli noLOF; Kotler NA; Kawaguchi NA; preliminary code BS3.
  • The TP53 VCEP BS3_Strong rule requires functional Kato data and no LOF by the majority of available eligible assays; the worksheet records this exact pattern.
  • The functional-rule flowchart was searched for c.877G>A, p.Gly293Arg, and p.G293R; no variant-specific entry was present, so the worksheet remains the governing variant-specific assignment.
  • The extracted Kato study describes the relevant TP53 transactivation assay system but does not explicitly mention G293R in the supplied extraction.
Still missing
  • No variant-specific entry for c.877G>A, p.Gly293Arg, or p.G293R was found in Flowchart-for-application-of-functional-rule-codes.pdf; Functional-worksheet.xlsx provides the governing pre-assigned BS3 code.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗
BP4 ModerateMet at moderate strength: the exact TP53 lookup assigns BP4_moderate with BayesDel -0.0095438 and class C0. Details ▾Hide ▴
Reasoning

This is a missense variant. The governing TP53 PP3-BP4-codes.xlsx lookup contains the exact c.877G>A / p.Gly293Arg entry and pre-assigns BP4_moderate, with BayesDel class C0 and score -0.0095438. Under the TP53 VCEP specification, this pre-assigned code is the governing answer and is applied directly; the absent SpliceAI result does not override the exact VCEP table assignment.

Rule
Apply the exact TP53 VCEP PP3-BP4-codes.xlsx pre-assignment for c.877G>A / p.Gly293Arg: BP4_moderate.
Evidence considered
  • The TP53 PP3-BP4-codes.xlsx exact row for c.877G>A / p.Gly293Arg reports Class C0, BayesDel -0.0095438, and pre-assigns BP4_moderate.
  • The governing VCEP lookup assignment outranks generic predictor thresholds and is applied directly.
  • SpliceAI returned no score for this variant; this is missing data, not evidence of absent splice impact, and does not negate the exact VCEP BP4_moderate assignment.
Still missing
  • No exact p.G293R notation was found in PP3-BP4-codes.xlsx; the exact c.877G>A / p.Gly293Arg row was found and is governing.
  • SpliceAI returned no score, so no independent splice-impact assessment is available; this does not block the exact VCEP pre-assignment.
Sources
vcep_pp3_bp4_codes

Not met · 7 · evaluated, threshold not reached

PS3 Not met: TP53 VCEP assigns BS3 because Kato is functional and Funk/Giacomelli are noLOF, with no majority-LOF pattern required for PS3. Details ▾Hide ▴
Reasoning

The TP53 VCEP Functional-worksheet.xlsx entry for p.G293R (NM_000546.6:c.877G>A; p.Gly293Arg) is pre-assigned BS3, not PS3: Kato is Functional, Funk and Giacomelli are noLOF, and Kawaguchi is NA. The governing TP53 PS3 rules require non-functional or partially functional Kato results together with majority-LOF eligible assays (or non-functional Kato plus abnormal Kawaguchi for PS3_Supporting), none of which is present. The Flowchart-for-application-of-functional-rule-codes.pdf was also searched under c.877G>A, p.Gly293Arg, and p.G293R and contains no variant-specific table entry. The extracted Kato paper likewise does not explicitly mention G293R, so it cannot independently override the VCEP worksheet assignment.

Rule
TP53 VCEP PS3: Strong = non-functional Kato AND majority LOF in other eligible assays; Moderate = partially functional Kato AND majority LOF; Supporting = non-functional Kato AND abnormal Kawaguchi regardless of other assays.
Evidence considered
  • Functional-worksheet.xlsx directly lists G293R as: Kato Functional; Funk noLOF; Giacomelli noLOF; Kotler NA; Kawaguchi NA; preliminary code BS3.
  • The TP53 VCEP PS3 rule requires non-functional Kato plus majority LOF in other eligible assays, or partially functional Kato plus majority LOF, with PS3_Supporting additionally allowing non-functional Kato plus abnormal Kawaguchi; the observed assay pattern meets none of these paths.
  • The functional-rule flowchart was searched for c.877G>A, p.Gly293Arg, and p.G293R; no variant-specific entry was present.
  • The extracted Kato study describes a comprehensive TP53 missense transactivation library but does not explicitly mention G293R or provide a variant-specific result in the supplied extraction.
Still missing
  • No variant-specific entry for c.877G>A, p.Gly293Arg, or p.G293R was found in Flowchart-for-application-of-functional-rule-codes.pdf; the worksheet assignment is nevertheless directly applicable.
  • Kawaguchi data are listed as NA for p.G293R, so the TP53 PS3_Supporting pathway requiring abnormal Kawaguchi data is unavailable.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗
PM1 Not met: p.Gly293Arg is at codon 293, outside the six TP53 PM1 codons, and cancerhotspots returned no significant hotspot for TP53 G293. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP specifies PM1_Moderate for missense variants at codons 175, 245, 248, 249, 273, or 282, and permits PM1 based on a cancerhotspots.org same-amino-acid count of at least 10. The variant is p.Gly293Arg at codon 293, outside all six specified codons. The cancerhotspots query for TP53 G293 returned no statistically significant hotspot row; the separate COSMIC record reports six somatic occurrences but does not satisfy the VCEP cancerhotspots threshold or substitute for the specified hotspot rule. The vcep_materials domain_tables object contains no TP53 entry, so there is no additional authoritative domain-table interval to assess.

Rule
TP53 VCEP PM1_Moderate: missense at codons 175, 245, 248, 249, 273, or 282; alternatively, same amino-acid change in cancerhotspots.org with at least 10 somatic occurrences.
Evidence considered
  • The TP53 VCEP PM1 rule lists codons 175, 245, 248, 249, 273, and 282 for PM1_Moderate and allows a same-amino-acid cancerhotspots.org count of at least 10 as an alternative route.
  • The variant residue is G293, and vcep_materials.json has an empty domain_tables object for TP53; therefore no domain-table interval applies beyond the explicit TP53 codon rule.
  • The cancerhotspots result for TP53 G293 was no result and stated that the variant does not lie in a statistically significant hotspot.
  • COSMIC reports COSV52752246 with six somatic occurrences, below the TP53 VCEP threshold of at least 10 and from a different source type.
Sources
vcep_outputfinal_classification_frameworkvcep_hotspots_vision_instruction
PP3 Not met: the exact TP53 lookup entry reports BayesDel -0.0095438, below the VCEP PP3 missense threshold of 0.16, and assigns BP4_moderate instead. Details ▾Hide ▴
Reasoning

This is a missense variant, so PP3 would ordinarily use the missense path. The governing TP53 PP3-BP4 lookup was searched for c.877G>A, p.Gly293Arg, and p.G293R; its exact c.877G>A / p.Gly293Arg entry is Class C0 with BayesDel -0.0095438 and assigns BP4_moderate, not PP3. The TP53 PP3 rules require BayesDel >=0.16 for missense PP3 assignments, and the observed score is below that threshold. SpliceAI returned no score, but that missing result is not used to assess this missense PP3 criterion.

Rule
TP53 VCEP PP3 missense rule: PP3_moderate requires aGVGD Class C65 and BayesDel >=0.16; PP3_supporting requires aGVGD Class C25-C55 and BayesDel >=0.16. The exact governing lookup entry instead assigns BP4_moderate.
Evidence considered
  • The TP53 PP3-BP4-codes.xlsx exact row for c.877G>A / p.Gly293Arg reports Class C0, BayesDel -0.0095438, and BP4_moderate.
  • The TP53 framework's missense PP3 assignments require BayesDel >=0.16; this variant's BayesDel score is -0.0095438.
  • SpliceAI returned no score for this variant, which is missing data rather than evidence for or against PP3; the missense criterion is evaluated on the governing missense lookup path.
Still missing
  • No exact p.G293R notation was found in PP3-BP4-codes.xlsx; the exact c.877G>A / p.Gly293Arg row was found and is governing.
Sources
vcep_pp3_bp4_codes
PP5 Not met: exact-match ClinVar variation 230208 has zero Expert Panel submissions and no Expert Panel Pathogenic or Likely Pathogenic classification. Details ▾Hide ▴
Reasoning

PP5 is restricted here to an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely Pathogenic. ClinVar variation 230208 exactly matches NM_000546.6:c.877G>A (p.Gly293Arg), but it has no Expert Panel submissions and reports only single-submitter classifications: Uncertain significance and Likely benign. Ordinary laboratory submissions and aggregate ClinVar labels do not satisfy the required Expert Panel condition, so PP5 is not met.

Rule
Apply PP5 only for an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely Pathogenic.
Evidence considered
  • ClinVar variation 230208 exactly matches NM_000546.6:c.877G>A (p.Gly293Arg), but the record reports zero Expert Panel submissions.
  • The available ClinVar submissions are single-laboratory assertions classified as Uncertain significance or Likely benign; these are not eligible to trigger PP5 under the requested rule.
Sources
clinvar ↗
BA1 Not met: highest qualifying population frequency was 3.2759e-05, below the TP53 VCEP BA1 FAF threshold of 0.001, with only one observed allele. Details ▾Hide ▴
Reasoning

The TP53 VCEP BA1 rule requires filtering allele frequency (FAF) of at least 0.001 in a qualifying continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles, excluding founder-effect groups. In gnomAD v2.1 non-cancer exomes, the highest observed ancestry frequency is South Asian 1/30,526 = 3.2759e-05, with only one allele; gnomAD v4.1 reports grpmax FAF 2.8e-07. These data are far below the VCEP BA1 threshold and do not satisfy its allele-count requirement.

Rule
TP53 VCEP BA1: filtering allele frequency (FAF) >=0.001 in a qualifying continental ancestry group; group must have >=2,000 alleles tested and >=2 variant alleles; exclude founder-effect groups.
Evidence considered
  • The TP53 Expert Panel specification defines BA1 as FAF >=0.001 in a single non-founder continental ancestry group, requiring >=2,000 alleles tested and at least 2 variant alleles.
  • gnomAD v2.1 non-cancer exomes show 2/236,948 total alleles and a highest ancestry frequency of 1/30,526 = 3.2758959575443885e-05 in South Asian individuals; the highest ancestry group has only one variant allele.
  • gnomAD v4.1 reports grpmax FAF = 2.8e-07, also below the VCEP BA1 threshold.
Sources
final_classification_frameworkgnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: maximum observed ancestry frequency was 3.2759e-05, below the TP53 VCEP BS1 FAF threshold of 0.0003 and based on one allele. Details ▾Hide ▴
Reasoning

The TP53 VCEP BS1 rule requires FAF of at least 0.0003 but less than 0.001 in a qualifying non-founder continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles. The gnomAD v2.1 non-cancer exome maximum observed ancestry frequency is South Asian 3.2759e-05 from one allele, and gnomAD v4.1 grpmax FAF is 2.8e-07. Neither reaches the VCEP BS1 threshold, and the v2 maximum does not meet the required two-allele condition.

Rule
TP53 VCEP BS1: 0.0003 <= FAF < 0.001 in a qualifying continental ancestry group; group must have >=2,000 alleles tested and >=2 variant alleles; exclude founder-effect groups.
Evidence considered
  • The TP53 Expert Panel specification defines BS1 as FAF >=0.0003 and <0.001 in a single non-founder continental ancestry group, requiring >=2,000 alleles tested and at least 2 variant alleles.
  • gnomAD v2.1 non-cancer exomes show a maximum ancestry frequency of 1/30,526 = 3.2758959575443885e-05 in South Asian individuals, below 0.0003 and with only one variant allele.
  • gnomAD v4.1 reports grpmax FAF = 2.8e-07, below the VCEP BS1 threshold.
Sources
final_classification_frameworkgnomad_v2 ↗gnomad_v4 ↗
BP6 Not met: ClinVar exact-match variation 230208 has no Expert Panel submission, so its single-submitter Likely benign assertion cannot trigger BP6. Details ▾Hide ▴
Reasoning

BP6 is restricted here to an exact-variant ClinVar Expert Panel classification of Benign or Likely benign. ClinVar variation 230208 exactly matches NM_000546.6:c.877G>A (p.Gly293Arg), but it has no Expert Panel submissions. The single-submitter Likely benign assertion cannot trigger BP6 under the required rule, and the remaining submissions are Uncertain significance.

Rule
Apply BP6 only for an exact-variant ClinVar Expert Panel classification of Benign or Likely benign.
Evidence considered
  • ClinVar variation 230208 exactly matches NM_000546.6:c.877G>A (p.Gly293Arg) and has zero Expert Panel submissions.
  • One ordinary single-submitter assertion is Likely benign, while the other submissions are Uncertain significance; ordinary submissions do not satisfy the required BP6 Expert Panel condition.
Sources
clinvar ↗

Not assessed · 8 · no assessment recorded

PS1 Not assessed: no qualifying pathogenic or likely pathogenic variant producing the same amino-acid change as p.Gly293Arg is documented in the reviewed evidence. Details ▾Hide ▴
Reasoning

The variant is TP53 p.Gly293Arg. PS1 requires a previously established pathogenic or likely pathogenic variant producing the same amino-acid change. The reviewed variant-specific and extracted literature sources do not document another qualifying p.Gly293Arg observation, and no validated same-amino-acid comparator is available in the supplied evidence. Therefore PS1 cannot be applied, but the absence of a qualifying comparator is not treated as definitive evidence against PS1.

Rule
TP53 VCEP PS1: same amino-acid change may receive Strong when the comparator is pathogenic or Moderate when the comparator is likely pathogenic according to TP53 VCEP specifications.
Evidence considered
  • The TP53 VCEP rule permits PS1 at strong strength for variants asserted pathogenic and at moderate strength for variants asserted likely pathogenic under the VCEP specifications; it does not supply a qualifying same-amino-acid comparator for p.Gly293Arg.
  • ClinVar variation 230208 is the queried p.Gly293Arg record and reports conflicting single-submitter classifications, not an independent same-amino-acid pathogenic comparator.
Still missing
  • A validated VCEP-eligible same-amino-acid comparator for p.Gly293Arg was not identified.
Sources
vcep_outputclinvar ↗
PS2 Not assessed: no proband cancer, de novo observation, or parental testing is documented, so the VCEP PS2 point thresholds cannot be applied. Details ▾Hide ▴
Reasoning

The TP53 VCEP governs PS2 by proband cancer points when maternity and paternity are confirmed or assumed: 1 point supports PS2, 2-3 points supports PS2_Moderate, 4-7 points supports PS2, and at least 8 points supports PS2_Very Strong. The available case materials contain no proband cancer history, de novo observation, or confirmed parental testing for NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R), so no PS2 points can be assigned. The governing table was searched for c.877G>A, p.Gly293Arg, and p.G293R and contains no variant-specific row; it supplies only the general cancer-point framework.

Rule
PS2: Supporting = 1 point; Moderate = 2-3 points; Strong = 4-7 points; Very Strong = >=8 points, using the TP53 LFS cancer point table.
Evidence considered
  • The TP53 VCEP table assigns 4 points for a strongly associated cancer when maternity and paternity are confirmed, 2 points when they are assumed, 2 points for a moderately associated cancer when maternity and paternity are confirmed, and 1 point when they are assumed.
  • The same table defines PS2_Supporting as 1 point, PS2_Moderate as 2-3 points, PS2 as 4-7 points, and PS2_Very Strong as at least 8 points.
  • No case-specific proband, parental, or de novo evidence was identified for this variant.
Still missing
  • No proband cancer diagnosis, age, or maternity/paternity confirmation is available to calculate PS2 points.
  • No parental testing or documented de novo status is available for NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R).
  • No variant-specific entry was found after searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt for c.877G>A, p.Gly293Arg, and p.G293R; the file contains general PS2 point rules only.
Sources
vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_applicationfinal_classification_framework
PS4 Not assessed: no proband phenotype or PS4 point total is available, and the searched PS4-Points-Table.pdf has no c.877G>A, p.Gly293Arg, or p.G293R entry. Details ▾Hide ▴
Reasoning

The TP53 VCEP PS4-Points-Table.pdf governs this criterion and assigns points per proband for Revised Chompret criteria (0.5), classic LFS criteria (1), and HER2-positive breast cancer diagnosed before age 40 (0.5), with PS4 Supporting at 1-1.5 points, Moderate at 2-3.5, Strong at 4-7.5, and Very Strong at >=8 points. The searched file has no variant-specific entry for c.877G>A, p.Gly293Arg, or p.G293R; it is a phenotype scoring table rather than a variant list. The case evidence supplies no proband cancer phenotype, LFS clinical-criteria assessment, or per-proband point total. The reviewed papers do not report this exact variant: PMID:1686725 reports the different p.Gly293Trp variant, PMID:21343334 evaluates a TP53 germline cohort without G293R, and PMID:23894400 reports a sarcoma cohort without G293R. Therefore PS4 cannot be assessed from the available phenotype evidence.

Rule
TP53 VCEP PS4 point total: Supporting = 1-1.5 points; Moderate = 2-3.5 points; Strong = 4-7.5 points; Very Strong >= 8 points.
Evidence considered
  • The TP53 PS4-Points-Table.pdf assigns 0.5 points for Revised Chompret criteria, 1 point for classic LFS criteria, and 0.5 points for HER2-positive breast cancer diagnosed before age 40; PS4 thresholds are Supporting 1-1.5, Moderate 2-3.5, Strong 4-7.5, and Very Strong >=8 points.
  • The exact variant notations c.877G>A, p.Gly293Arg, and p.G293R were searched in PS4-Points-Table.pdf; no variant-specific entry was found.
  • PMID:1686725 reports p.Gly293Trp, not p.Gly293Arg; PMID:21343334 and PMID:23894400 describe TP53 cohorts without an exact G293R observation.
Still missing
  • No proband cancer phenotype or Revised Chompret/classic LFS assessment was provided for PS4 point assignment.
  • No per-proband PS4 point total is available.
  • The searched file PS4-Points-Table.pdf contains no entry for c.877G>A, p.Gly293Arg, or p.G293R.
  • PMID:1686725, PMID:21343334, and PMID:23894400 were reviewed for exact-variant phenotype evidence; none reports p.Gly293Arg/p.G293R.
Sources
vcep_ps4_points_tablePMID:1686725 ↗PMID:21343334 ↗PMID:23894400 ↗
PM5 Not assessed: p.Gly293Trp is reported at residue 293, but its pathogenicity is unestablished and the same-residue search ended with an HTTP 429 error. Details ▾Hide ▴
Reasoning

PM5 requires a different missense variant at the same amino-acid residue that was previously determined pathogenic, likely pathogenic, or likely pathogenic with qualifying clinical data, with strength based on the number and classification of such variants. The reviewed paper extract reports TP53 p.Gly293Trp at the same residue, but does not establish it as pathogenic or likely pathogenic and provides no completed functional result. The automated same-residue candidate collection found no qualifying candidates but ended with an HTTP 429 error, so the evidence is insufficient to conclude that no eligible comparator exists.

Rule
TP53 VCEP PM5: one different pathogenic same-residue missense variant supports Moderate; at least two support Strong; one clinically supported likely pathogenic same-residue variant supports Supporting.
Evidence considered
  • The TP53 VCEP PM5 rule requires one different pathogenic missense variant at the same residue for PM5_Moderate, at least two different pathogenic variants for PM5_Strong, or one clinically supported likely pathogenic variant for PM5_Supporting.
  • The same-residue candidate artifact reports zero same-residue candidates and warns that candidate harvesting failed softly because of HTTP Error 429; it is not sufficient for a definitive negative PM5 conclusion.
  • PMID:1686725 reports a different codon 293 substitution, p.Gly293Trp, in an astrocytoma case and describes loss of the wild-type allele, but does not provide a completed functional assay or a VCEP-eligible pathogenic/likely pathogenic classification.
Still missing
  • A complete VCEP-eligible review of all alternate missense variants at TP53 residue 293 is still required.
  • The p.Gly293Trp report lacks a qualifying pathogenic or likely pathogenic determination under the TP53 VCEP rule.
Sources
vcep_outputpm5_candidatesPMID:1686725 ↗
PP1 Not assessed: no relatives, meioses, or cosegregation data are documented, so the VCEP PP1 thresholds cannot be applied. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires cosegregation across meioses: 3-4 meioses for PP1_Supporting, 5-6 meioses for PP1_Moderate, and at least 7 meioses across more than one family for PP1_Strong. No affected or unaffected relatives, genotype-phenotype relationships, meioses, or family segregation data are documented for NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R), so PP1 cannot be assigned. The governing PS2/PP1 table was searched for c.877G>A, p.Gly293Arg, and p.G293R and contains no variant-specific row; it provides only the general cancer-point framework rather than segregation observations.

Rule
PP1: Supporting = 3-4 cosegregating meioses; Moderate = 5-6 meioses; Strong = >=7 meioses across >1 family.
Evidence considered
  • The TP53 VCEP requires 3-4 cosegregating meioses for PP1_Supporting, 5-6 meioses for PP1_Moderate, and at least 7 meioses across more than one family for PP1_Strong.
  • No family segregation, genotype, phenotype, or meiosis data were identified for this variant.
Still missing
  • No family pedigree or affected-relative genotype/phenotype data are available.
  • No count of informative meioses or cosegregation across families is available.
  • No variant-specific entry was found after searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt for c.877G>A, p.Gly293Arg, and p.G293R; the file contains general PS2/PP1 guidance only.
Sources
vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_applicationfinal_classification_frameworkPMID:1686725 ↗PMID:21343334 ↗PMID:23894400 ↗
PP4 Not assessed: no PP4-qualifying VAF observation is available; the framework requires VAF 5-35% for Supporting or at least two 5-25% observations for Moderate. Details ▾Hide ▴
Reasoning

The governing TP53 framework specifies PP4 as pathogenic supporting by default, with Moderate requiring at least 2 independent observations of the variant with VAF 5-25% and Supporting requiring observation of the variant with VAF 5-35%. No VAF measurements, independent observations, or other PP4-qualifying clinical observations for c.877G>A/p.Gly293Arg are present in the case evidence. The exact variant is not reported in the reviewed paper extracts. PP4 therefore cannot be assessed.

Rule
PP4 default strength Supporting; Moderate requires at least 2 independent observations with VAF 5-25%; Supporting requires observation with VAF 5-35%.
Evidence considered
  • The TP53 framework states PP4 Moderate requires at least 2 independent observations with VAF 5-25%, while PP4 Supporting requires observation with VAF 5-35%.
  • The case evidence contains no VAF value or independent-observation count for NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R).
Still missing
  • No VAF measurement or independent-observation count is available for the exact variant.
  • No exact-variant PP4 clinical observation was found in the reviewed paper extracts.
BS2 Not assessed: no single-source records identify at least two unrelated cancer-free females aged 60 years or older carrying this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP BS2 rule requires observations from one source of at least 2 unrelated females aged 60 years or older without cancer for supporting strength, 4-7 for moderate, or at least 8 for strong; females with sarcoma at age 61 years or older are excluded. The available population records provide allele counts and homozygote counts but no qualifying individual-level age, sex, cancer-history, source, or relatedness information, so BS2 cannot be adjudicated.

Rule
TP53 VCEP BS2: same-source observations of unrelated females >=60 years without cancer; Supporting 2-3, Moderate 4-7, Strong >=8; exclude individuals with sarcoma diagnosed at >=61 years.
Evidence considered
  • The TP53 Expert Panel specification requires 2-3 qualifying females from one source for BS2 Supporting, 4-7 for Moderate, or at least 8 for Strong; all must be unrelated, female, aged at least 60 years, and without cancer.
  • gnomAD v2.1 and v4.1 report zero homozygotes but do not provide the individual-level demographic and clinical details required for the TP53 BS2 rule.
Still missing
  • Individual-level BS2 evidence from one source, including sex, age >=60, cancer-free status, unrelatedness, and exclusion of late sarcoma, is unavailable.
Sources
final_classification_frameworkgnomad_v2 ↗gnomad_v4 ↗
BS4 Not assessed: no affected-relative genotypes or documented non-segregation are available for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP defines BS4 as strong evidence for lack of segregation in affected family members diagnosed with LFS-associated cancers. No affected relatives, family genotypes, non-segregation observations, or relevant cancer diagnoses are documented for NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R). The exact-variant literature review found no qualifying family evidence: PMID:1686725 reports a different codon-293 substitution, p.Gly293Trp, and PMID:21343334 and PMID:23894400 do not explicitly mention this variant. Thus BS4 cannot be assessed.

Rule
BS4: Strong when lack of segregation is observed in affected family members diagnosed with LFS-associated cancers.
Evidence considered
  • The TP53 VCEP defines BS4 as lack of segregation in affected family members with LFS-associated cancers.
  • PMID:1686725 reports a different codon-293 variant, p.Gly293Trp, found in a patient and his father; it is not evidence about p.Gly293Arg.
  • PMID:21343334 evaluates TP53 germline alleles in a functional cohort but does not explicitly mention p.Gly293Arg.
  • PMID:23894400 reports a sarcoma cohort and germline TP53 findings but does not explicitly mention p.Gly293Arg.
Still missing
  • No family genotyping and no affected-relative cancer/genotype comparison are available.
  • No documented lack of segregation for NM_000546.6:c.877G>A (p.Gly293Arg/p.G293R) is available.
  • PMID:1686725 was reviewed but reports p.Gly293Trp, not this variant; PMID:21343334 and PMID:23894400 do not explicitly mention this variant.
Sources
final_classification_frameworkvcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_applicationPMID:1686725 ↗PMID:21343334 ↗PMID:23894400 ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.877G>A is a missense variant producing p.Gly293Arg, outside the TP53 VCEP PVS1 null-variant and splice-site rules. Details ▾Hide ▴
Reasoning

PVS1 is not applicable because NM_000546.6:c.877G>A (NP_000537.3:p.(Gly293Arg), p.G293R) is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or copy-number null variant. The TP53 VCEP PVS1 flowchart governs null variants and therefore does not assign PVS1 to this consequence. The required searches found no direct entry for c.877G>A, p.Gly293Arg, or p.G293R in PVS1-Flowchart.pdf.txt or PVS1-Splicing-Worksheet.xlsx.txt; this is a lookup result, not evidence of absent disease impact.

Evidence considered
  • The TP53 VCEP framework defines PVS1 for null variants, including nonsense, frameshift, canonical splice-site, initiation-codon, and copy-number variants; it does not apply to a missense substitution.
  • Case normalization identifies NM_000546.6:c.877G>A as NP_000537.3:p.(Gly293Arg), p.G293R, with consequence class missense.
Still missing
  • No entry for c.877G>A, p.Gly293Arg, or p.G293R was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/TP53/fulltext/PVS1-Flowchart.pdf.txt.
  • No entry for c.877G>A, p.Gly293Arg, or p.G293R was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/TP53/fulltext/PVS1-Splicing-Worksheet.xlsx.txt.
Sources
pvs1_gene_contextvcep_pvs1_flowchart
PM3 VCEPNot applicable: the TP53 Expert Panel Version 2.4 framework explicitly designates PM3 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing TP53 Expert Panel framework, Version 2.4, explicitly designates PM3 as Not Applicable. Therefore, phase, affected-proband observations, and the presence or absence of pathogenic variants in trans or cis are not used to apply PM3 for this TP53 variant.

VCEP rule
Not Applicable under the TP53 Expert Panel Version 2.4 framework.
Evidence considered
  • The TP53 Expert Panel Version 2.4 criterion specification lists PM3 with applicability set to Not Applicable.
  • No phase or trans/cis evidence is needed to resolve PM3 because the governing TP53 specification excludes this criterion.
Sources
final_classification_framework
PM4 VCEPNot applicable: the single-nucleotide missense substitution p.Gly293Arg does not alter protein length through an in-frame indel or stop-loss event. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the TP53 VCEP framework. The variant is a single-nucleotide missense substitution, c.877G>A, producing p.Gly293Arg, and does not cause a protein-length change through an in-frame deletion, insertion, indel, or stop-loss event.

Evidence considered
  • The TP53 VCEP framework marks PM4 as not applicable for this variant assessment, and the normalized consequence is missense rather than an in-frame protein-length-changing event.
Sources
final_classification_framework
PM6 VCEPNot applicable: the governing TP53 framework explicitly designates PM6 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing TP53 framework explicitly marks PM6 as Not Applicable. Therefore generic ACMG PM6 criteria are not substituted, regardless of the absence of parental testing or a documented de novo observation.

VCEP rule
PM6: Not Applicable under the governing TP53 framework.
Evidence considered
  • The governing TP53 framework lists PM6 with applicability Not Applicable.
Sources
final_classification_framework
PP2 VCEPNot applicable: the governing TP53 VCEP explicitly marks PP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP explicitly marks PP2 as Not Applicable. Generic ACMG PP2 is therefore not used.

VCEP rule
TP53 VCEP PP2: Not Applicable.
Evidence considered
  • The TP53 VCEP framework lists PP2 with applicability Not Applicable.
Sources
vcep_output
BP1 VCEPNot applicable: the governing TP53 VCEP explicitly marks BP1 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing TP53 VCEP explicitly marks BP1 as Not Applicable. Generic ACMG BP1 is therefore not used.

VCEP rule
TP53 VCEP BP1: Not Applicable.
Evidence considered
  • The TP53 VCEP framework lists BP1 with applicability Not Applicable.
Sources
vcep_output
BP2 VCEPNot applicable: the TP53 Expert Panel Version 2.4 framework explicitly designates BP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing TP53 Expert Panel framework, Version 2.4, explicitly designates BP2 as Not Applicable. Therefore, observations of this variant with another pathogenic variant in cis or trans are not used to apply BP2 for this TP53 variant.

VCEP rule
Not Applicable under the TP53 Expert Panel Version 2.4 framework.
Evidence considered
  • The TP53 Expert Panel Version 2.4 criterion specification lists BP2 with applicability set to Not Applicable.
  • No cis/trans allelic observation is needed to resolve BP2 because the governing TP53 specification excludes this criterion.
Sources
final_classification_framework
BP3 VCEPNot applicable: p.Gly293Arg is a missense substitution, not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the TP53 VCEP framework. The variant is a missense substitution, c.877G>A (p.Gly293Arg), not an in-frame deletion or insertion located in a repetitive region with no functional impact.

Evidence considered
  • The TP53 VCEP framework marks BP3 as not applicable for this variant assessment, and no in-frame indel or repeat-region protein-length change is present.
Sources
final_classification_framework
BP5 VCEPNot applicable: the governing TP53 framework explicitly marks BP5 as Not Applicable. Details ▾Hide ▴
Reasoning

The TP53 VCEP framework marks BP5 as Not Applicable. No BP5-specific governing rule is available for this case, so BP5 is not applicable rather than assessed using a generic rule.

VCEP rule
TP53 VCEP BP5: Not Applicable.
Evidence considered
  • The governing TP53 framework lists BP5 as Not Applicable.
BP7 N/ANot applicable: c.877G>A is a missense variant producing p.Gly293Arg, whereas BP7 applies only to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_000546.6:c.877G>A is a missense variant producing p.Gly293Arg, so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 applies only to synonymous or qualifying intronic variants; missense variants are out of scope.
Evidence considered
  • Case normalization identifies NM_000546.6:c.877G>A as a missense variant producing NP_000537.3:p.(Gly293Arg).

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.877G>A
Protein (HGVS p.)
NP_000537.3:p.(Gly293Arg)
GRCh38
chr17:7673743 C>T
GRCh37
chr17:7577061 C>T
Location and type
Exon 8 · missense
ClinVar
230208
COSMIC
COSV52752246

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.

TP53NM_000546.6
Fetching transcript structure from UCSC…
gnomAD v4.1 3 / 1,614,170 alleles AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1 2 / 251,482 alleles AF 7.95e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,170 alleles · 0 hom · FAF 2.8e-07
South Asian1 / 91,084 1.1e-05
European (non-Finnish)2 / 1,180,028 1.7e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,482 alleles · 0 hom
South Asian1 / 30,616 3.3e-05
European (non-Finnish)1 / 113,758 8.8e-06
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85854e-06; MAF= 0.00019%, 3/1614170 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09789e-05; MAF= 0.00110%, 1/91084 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95286e-06; MAF= 0.00080%, 2/251482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.005
Pangolin splice gain
0.002

Other predictors

REVEL
0.402
BayesDel
-0.010

How the predictions were used

BP4 ModerateMet at moderate strength: the exact TP53 lookup assigns BP4_moderate with BayesDel -0.0095438 and class C0. Details ▾Hide ▴
Reasoning

This is a missense variant. The governing TP53 PP3-BP4-codes.xlsx lookup contains the exact c.877G>A / p.Gly293Arg entry and pre-assigns BP4_moderate, with BayesDel class C0 and score -0.0095438. Under the TP53 VCEP specification, this pre-assigned code is the governing answer and is applied directly; the absent SpliceAI result does not override the exact VCEP table assignment.

Rule
Apply the exact TP53 VCEP PP3-BP4-codes.xlsx pre-assignment for c.877G>A / p.Gly293Arg: BP4_moderate.
Evidence considered
  • The TP53 PP3-BP4-codes.xlsx exact row for c.877G>A / p.Gly293Arg reports Class C0, BayesDel -0.0095438, and pre-assigns BP4_moderate.
  • The governing VCEP lookup assignment outranks generic predictor thresholds and is applied directly.
  • SpliceAI returned no score for this variant; this is missing data, not evidence of absent splice impact, and does not negate the exact VCEP BP4_moderate assignment.
Still missing
  • No exact p.G293R notation was found in PP3-BP4-codes.xlsx; the exact c.877G>A / p.Gly293Arg row was found and is governing.
  • SpliceAI returned no score, so no independent splice-impact assessment is available; this does not block the exact VCEP pre-assignment.
Sources
vcep_pp3_bp4_codes
PP3 Not met: the exact TP53 lookup entry reports BayesDel -0.0095438, below the VCEP PP3 missense threshold of 0.16, and assigns BP4_moderate instead. Details ▾Hide ▴
Reasoning

This is a missense variant, so PP3 would ordinarily use the missense path. The governing TP53 PP3-BP4 lookup was searched for c.877G>A, p.Gly293Arg, and p.G293R; its exact c.877G>A / p.Gly293Arg entry is Class C0 with BayesDel -0.0095438 and assigns BP4_moderate, not PP3. The TP53 PP3 rules require BayesDel >=0.16 for missense PP3 assignments, and the observed score is below that threshold. SpliceAI returned no score, but that missing result is not used to assess this missense PP3 criterion.

Rule
TP53 VCEP PP3 missense rule: PP3_moderate requires aGVGD Class C65 and BayesDel >=0.16; PP3_supporting requires aGVGD Class C25-C55 and BayesDel >=0.16. The exact governing lookup entry instead assigns BP4_moderate.
Evidence considered
  • The TP53 PP3-BP4-codes.xlsx exact row for c.877G>A / p.Gly293Arg reports Class C0, BayesDel -0.0095438, and BP4_moderate.
  • The TP53 framework's missense PP3 assignments require BayesDel >=0.16; this variant's BayesDel score is -0.0095438.
  • SpliceAI returned no score for this variant, which is missing data rather than evidence for or against PP3; the missense criterion is evaluated on the governing missense lookup path.
Still missing
  • No exact p.G293R notation was found in PP3-BP4-codes.xlsx; the exact c.877G>A / p.Gly293Arg row was found and is governing.
Sources
vcep_pp3_bp4_codes
BP7 N/ANot applicable: c.877G>A is a missense variant producing p.Gly293Arg, whereas BP7 applies only to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_000546.6:c.877G>A is a missense variant producing p.Gly293Arg, so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 applies only to synonymous or qualifying intronic variants; missense variants are out of scope.
Evidence considered
  • Case normalization identifies NM_000546.6:c.877G>A as a missense variant producing NP_000537.3:p.(Gly293Arg).

Statement

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.402. BayesDel score = -0.0095438.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
    Kato S et al. · 2003
    The paper describes a comprehensive yeast-based transactivation analysis of 2,314 TP53 missense mutants, but the supplied extraction does not explicitly mention c.877G>A, p.Gly293Arg, or p.G293R and provides no variant-specific functional result for G293R.
    Does not name this variant
    PMID 12826609 ↗
    Quoted passage
    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.

    Results, “Construction of 2,314 Distinct p53 Missense Mutations”

  • TP53 gene mutations and 17p deletions in human astrocytomas.
    Chung R et al. · 1991
    This paper reports a different TP53 missense change at the same residue, p.Gly293Trp, in an astrocytoma case. The alteration was heterozygous in constitutional leukocyte DNA, the tumor lost the wild-type allele, and the alteration was absent from 110 unrelated control alleles; the paper states that in-vitro transformation testing was ongoing and does not provide a completed functional result or a VCEP-eligible pathogenic classification.
    Does not name this variant
    PMID 1686725 ↗
    Quoted passage
    Transversion of G to T in exon 7, codon 293, alters the encoded amino acid from glycine to tryptophan (Fig 1C). This sequence was present as a heterozygous alteration in the constitutional (leukocyte) DNA of this patient; however, the tumor exhibited specific loss of the wild-type TP53 allele, leaving only the mutant allele. This alteration was not seen in the sequence of 110 unrelated alleles, strongly suggesting that it represents an aberration rather than a common polymorphism. This sequence is currently being tested for in vitro transformation properties.

    Results, paragraph describing glioblastoma GJB7; Figure 1C

  • Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.
    Monti P et al. · 2011
    This paper does not explicitly mention TP53 c.877G>A or NP_000537.3:p.(G293R). It evaluates 104 germline TP53 single-amino-acid mutant alleles using yeast-based luciferase assays measuring transactivation and dominant-negative effects; it provides no variant-specific segregation, de novo, or family observation for p.Gly293Arg.
    Does not name this variant
    PMID 21343334 ↗
    Quoted passage
    Of the remaining 103 alleles, 69 were classified as SD (mean activity <25% of wild-type) and 34 as PD (mean activity >=25% of wild-type) (Table 1).

    Results, Analysis of transactivation of mutant TP53 germline alleles

  • ACMG recommendations for reporting of incidental findings in clinical exome and
    No paper-specific finding is recorded.
    PMID 23788249 ↗
  • High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort.
    Mitchell G et al. · 2013
    The paper does not explicitly mention TP53 c.877G>A or NP_000537.3:p.(G293R). It reports a systematic screen of 559 adults with sarcoma, identifying pathogenic or putatively pathogenic TP53 events in 20 probands, but provides no variant-specific segregation, de novo, or family observation for p.Gly293Arg.
    Does not name this variant
    PMID 23894400 ↗
    Quoted passage
    Pathogenic or putatively pathogenic TP53 events occurred in the peripheral blood DNA of 20/559 probands (3.6%), comprising 18 single nucleotide mutations or indels, and 2 whole gene deletions (Table 1).

    Results, paragraph 1

  • ACMG policy statement: updated recommendations regarding analysis and reporting
    No paper-specific finding is recorded.
    PMID 25356965 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint co
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Tes
    No paper-specific finding is recorded.
    PMID 26140447 ↗

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

gnomAD v4.1 3 / 1,614,170 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar 4 Uncertain significance · 1 Likely benign · 1 Uncertain Significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85854e-06; MAF= 0.00019%, 3/1614170 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09789e-05; MAF= 0.00110%, 1/91084 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95286e-06; MAF= 0.00080%, 2/251482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 230208)

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.402. BayesDel score = -0.0095438.

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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52752246, n = 6 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.