About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.293C>G, p.(Pro98Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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 v2.4.0. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
PM2_Supporting is met. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0 in all populations. This satisfies the VCEP PM2_Supporting threshold of an allele frequency less than 0.00003 (0.003%).
PP3Moderate
PP3 · moderate
PP3_Moderate is met. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G (p.Pro98Arg). This variant has aGVGD Class C65 and a BayesDel score of 0.591769 (≥0.16), satisfying the VCEP PP3_moderate rule. SpliceAI max delta score is 0.00 (<0.2), confirming no predicted splicing impact that would alter the code assignment. REVEL score of 0.955 provides additional in silico support.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + PP3 moderate (+2) = 3 points, which maps to VUS.
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.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV113304063, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2_Supporting is met: NM_000546.6:c.293C>G (p.Pro98Arg) is absent from gnomAD v2.1 and v4.1 (0 alleles across all populations), satisfying the VCEP PM2_Supporting threshold of allele frequency <0.00003.
PP3_Moderate is met: The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G. This variant has aGVGD Class C65 and BayesDel score 0.591769 (≥0.16), with no predicted splicing impact (SpliceAI max delta 0.00). REVEL score of 0.955 provides additional in silico support.
PVS1 is not applicable: this is a missense variant; the TP53 VCEP reserves PVS1 for null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletions).
PS3 and BS3 are not met: the VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg. Kato class is 'Partially functional' and Giacomelli reports 'noLOF', which does not satisfy VCEP PS3 or BS3 criteria thresholds.
PM1 is not met: codon 98 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282), and the residue is not a statistically significant hotspot on cancerhotspots.org. PM5 is not met: no other Pro98 missense variant has a VCEP P/LP classification.
PS1, PS2, PS4, PP1, PP4, BA1, BS1, BS2, BS3, BS4, BP4 are not met based on absence of qualifying evidence from ClinVar, gnomAD, published literature, and VCEP reference data.
PP5, BP1, BP2, BP5, BP6, PM6, PP2, and BP3 are not applicable under the TP53 VCEP v2.4.0 specifications. PS5 is not included in the VCEP criteria set. BP7 is not applicable as this is a missense variant.
Tavtigian point tally: PM2_Supporting (+1) + PP3_Moderate (+2) = 3 points. Per TP53 VCEP v2.4.0 ranges: ≥10 Pathogenic, 6-9 Likely Pathogenic, -1 to 5 Uncertain Significance, -6 to -2 Likely Benign, ≤-7 Benign. Total of 3 points classifies this variant as Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingPM2_Supporting is met. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0 in all populations. This satisfies the VCEP PM2_Supporting threshold of an allele frequency less than 0.00003 (0.003%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles)
- gnomAD v4.1: absent (0 alleles)
- gnomAD-Canada v1.0: absent (0 alleles)
- AF 0 << VCEP PM2_Supporting threshold of 0.00003
Sources
PP3 ModeratePP3_Moderate is met. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G (p.Pro98Arg). This variant has aGVGD Class C65 and a BayesDel score of 0.591769 (≥0.16), satisfying the VCEP PP3_moderate rule. SpliceAI max delta score is 0.00 (<0.2), confirming no predicted splicing impact that would alter the code assignment. REVEL score of 0.955 provides additional in silico support. Details ▾Hide ▴
Evidence considered
- PP3-BP4-codes.xlsx: pre-assigned code = PP3_moderate
- aGVGD: Class C65
- BayesDel: 0.591769 (≥0.16 VCEP threshold)
- REVEL: 0.955
- SpliceAI max delta: 0.00 (<0.2
- no splicing impact)
Sources
Not met · 14 · evaluated, threshold not reached
PS1 PS1 is not met. No other missense variant at codon Pro98 has been classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. The VCEP Functional worksheet assigns 'No evidence' to all tested Pro98 variants (P98A, P98H, P98L, P98S, P98T), and no Pro98 variant has a VCEP-established pathogenic classification. Details ▾Hide ▴
Evidence considered
- Functional-worksheet.xlsx: all Pro98 variants coded 'No evidence'
- PM5 candidates: 0 expert_panel_plp_candidates at this residue
Sources
vcep_functional_worksheetcspec ↗
PS2 PS2 is not met. No de novo occurrence with confirmed maternity and paternity has been identified for this variant in ClinVar submissions, the published literature, or the IARC TP53 database. Details ▾Hide ▴
PS3 PS3 is not met. The VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg. Kato et al. (PMID:12826609) classifies this variant as 'Partially functional', and Giacomelli et al. (PMID:30224644) reports 'noLOF'. Under VCEP rules, PS3_Moderate requires LOF by majority of other available assays (not met; only Giacomelli has data and shows noLOF), and PS3_Supporting requires Kato to be non-functional (not met; Kato shows partially functional). No other eligible functional assays (Funk, Kotler, Kawaguchi) have data for this residue. Details ▾Hide ▴
Evidence considered
- Functional-worksheet.xlsx: P98R coded 'No evidence'
- Kato class: Partially functional
- Giacomelli class: noLOF
- Funk
- Kotler
- Kawaguchi: no data for this residue
Sources
PS4 PS4 is not met. No probands with specific Li-Fraumeni syndrome cancer diagnoses have been identified to allow case-count scoring under the VCEP PS4 point table (PS4-Points-Table.pdf). No case-control study has reported this variant in an affected cohort. ClinVar submissions do not provide quantifiable case counts with phenotype data. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 submissions
- both Uncertain significance
- no case counts with LFS cancer phenotypes
- Exploratory search: no published case-control study found
- COSMIC: 3 somatic occurrences
- but no germline proband data for PS4 scoring
Still missing
- No proband-level phenotype data available to apply VCEP PS4 cancer point scoring
Sources
PM1 PM1 is not met. Codon 98 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282). The residue is not listed as a statistically significant hotspot on cancerhotspots.org, and the COSMIC count of 3 somatic occurrences does not independently meet the VCEP PM1_Supporting threshold as the variant is not recognized in cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- VCEP PM1 hotspot codons: 175
- 245
- 248
- 249
- 273
- 282 — codon 98 not included
- Cancerhotspots.org: residue not significant
- exact variant not listed
- COSMIC: 3 somatic occurrences (COSV113304063)
Sources
PM5 PM5 is not met. No other missense variant at codon Pro98 has been classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. The VCEP Functional worksheet assigns 'No evidence' to all tested Pro98 alternative substitutions (P98A, P98H, P98L, P98S, P98T), and ClinVar contains no VCEP-level P/LP classifications for any Pro98 variant. Details ▾Hide ▴
Evidence considered
- PM5 candidates: 0 same-residue expert_panel_plp_candidates
- Functional-worksheet.xlsx: all Pro98 variants coded 'No evidence'
- No VCEP P/LP classification exists for any Pro98 variant
Sources
PP1 PP1 is not met. No cosegregation data have been identified for this variant in families with Li-Fraumeni syndrome or TP53-associated cancers. No published family studies or ClinVar submission annotations describe meiotic segregation data. Details ▾Hide ▴
PP4 PP4 is not met. No observations of this variant with documented variant allele fraction (VAF) data have been identified. The VCEP PP4 rule requires at least one observation with VAF 5-35% (supporting) or at least two independent observations with VAF 5-25% (moderate). No VAF data are available in ClinVar submissions or the literature. Details ▾Hide ▴
BA1 BA1 is not met. The variant is absent from gnomAD v2.1 and v4.1. The VCEP BA1 threshold requires a filtering allele frequency ≥0.001 in a single continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Absence from population databases precludes application of BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- FAF does not reach BA1 threshold of ≥0.001
Sources
BS1 BS1 is not met. The variant is absent from gnomAD. The VCEP BS1 threshold requires a filtering allele frequency ≥0.0003 but <0.001 in a single continental subpopulation. Zero alleles across all populations does not satisfy this criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- FAF of 0 does not reach BS1 threshold of ≥0.0003
Sources
BS2 BS2 is not met. No data have been identified describing unrelated healthy females aged ≥60 years without cancer who carry this variant. The VCEP BS2 rule requires at least 2 such individuals from a single source. No such observations exist in ClinVar or the literature. Details ▾Hide ▴
BS3 BS3 is not met. The VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg, which is the authoritative pre-assigned code. Although Kato et al. classifies this variant as 'Partially functional' and Giacomelli et al. reports 'noLOF' (which could nominally approach BS3_Supporting under VCEP rules), the VCEP expert panel's consolidated code 'No evidence' takes precedence and does not apply a benign functional code. Details ▾Hide ▴
Evidence considered
- Functional-worksheet.xlsx: P98R coded 'No evidence' (authoritative)
- Kato class: Partially functional
- Giacomelli class: noLOF
- Funk
- Kotler
- Kawaguchi: no data
Sources
BS4 BS4 is not met. No family data have been identified showing lack of segregation of this variant with Li-Fraumeni syndrome-associated cancers. No reports describe an unaffected family member carrying the variant in a family with a clear TP53-related phenotype. Details ▾Hide ▴
BP4 BP4 is not met. Under VCEP rules, BP4 is expressly excluded for aGVGD Class C65 variants: 'BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4).' Since this variant is classified as aGVGD Class C65, BP4 cannot be applied regardless of the BayesDel score. Details ▾Hide ▴
Evidence considered
- PP3-BP4-codes.xlsx: assigns PP3_moderate
- not BP4
- aGVGD: Class C65 — VCEP BP4 rule explicitly excludes C65 variants
- BayesDel: 0.591769 (not in BP4 range)
- SpliceAI: 0.00 (<0.2)
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable. This variant is a missense substitution (p.Pro98Arg), and the TP53 VCEP reserves PVS1 for null variants only: nonsense, frameshift, canonical splice ±1/2, initiation codon, and exon-level deletions. Details ▾Hide ▴
Evidence considered
- Variant is missense in exon 4
- not a null variant class
- PVS1 variant assessment confirms bucket='other'
- not nonsense/frameshift/canonical splice
Sources
PM6 VCEPPM6 is not applicable. The TP53 VCEP v2.4.0 explicitly lists PM6 as Not Applicable. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable. The TP53 VCEP v2.4.0 explicitly lists PP2 as Not Applicable. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable. The TP53 VCEP v2.4.0 explicitly lists PP5 as Not Applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP1 as Not Applicable. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP2 as Not Applicable. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable. In-frame deletions/insertions in a repetitive region without known function. This is a missense substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel
BP5 VCEPBP5 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP5 as Not Applicable. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP6 as Not Applicable. Details ▾Hide ▴
BP7 N/ABP7 is not applicable. This is a missense variant (p.Pro98Arg), not a synonymous/silent or intronic variant. The VCEP BP7 criterion applies only to synonymous (silent) variants outside the core splice motif or intronic variants at or beyond +7 to -21 positions. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.293C>G
- p.Pro98Arg)
- not synonymous or intronic
Sources
PS5 N/APS5 is not applicable. The TP53 VCEP v2.4.0 does not include PS5 in its criteria set; this criterion is not recognized by the expert panel specifications. Details ▾Hide ▴
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.293C>G
- Protein (HGVS p.)
- NP_000537.3:p.(Pro98Arg)
- GRCh38
- chr17:7676076 G>C
- GRCh37
- chr17:7579394 G>C
- ClinVar
- 1444043
- COSMIC
- COSV113304063
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…
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.955
- BayesDel
- 0.592
How the predictions were used
PP3 ModeratePP3_Moderate is met. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G (p.Pro98Arg). This variant has aGVGD Class C65 and a BayesDel score of 0.591769 (≥0.16), satisfying the VCEP PP3_moderate rule. SpliceAI max delta score is 0.00 (<0.2), confirming no predicted splicing impact that would alter the code assignment. REVEL score of 0.955 provides additional in silico support. Details ▾Hide ▴
Evidence considered
- PP3-BP4-codes.xlsx: pre-assigned code = PP3_moderate
- aGVGD: Class C65
- BayesDel: 0.591769 (≥0.16 VCEP threshold)
- REVEL: 0.955
- SpliceAI max delta: 0.00 (<0.2
- no splicing impact)
Sources
BP4 BP4 is not met. Under VCEP rules, BP4 is expressly excluded for aGVGD Class C65 variants: 'BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4).' Since this variant is classified as aGVGD Class C65, BP4 cannot be applied regardless of the BayesDel score. Details ▾Hide ▴
Evidence considered
- PP3-BP4-codes.xlsx: assigns PP3_moderate
- not BP4
- aGVGD: Class C65 — VCEP BP4 rule explicitly excludes C65 variants
- BayesDel: 0.591769 (not in BP4 range)
- SpliceAI: 0.00 (<0.2)
Sources
BP7 N/ABP7 is not applicable. This is a missense variant (p.Pro98Arg), not a synonymous/silent or intronic variant. The VCEP BP7 criterion applies only to synonymous (silent) variants outside the core splice motif or intronic variants at or beyond +7 to -21 positions. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.293C>G
- p.Pro98Arg)
- not synonymous or intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.955. BayesDel score = 0.591769.
9 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
-
PMID 12826609 ↗Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.Kato S et al. · 2003No paper-specific finding is recorded.
-
PMID 29979965 ↗A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.Kotler E et al. · 2018No paper-specific finding is recorded.
-
PMID 30224644 ↗Mutational processes shape the landscape of TP53 mutations in human cancer.Giacomelli AO et al. · 2018No paper-specific finding is recorded.
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
-
PMID 20301488 ↗Li-Fraumeni Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014No paper-specific finding is recorded.
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PMID 25394175 ↗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. · 2015No paper-specific finding is recorded.
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1444043/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579394-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7676076-G-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.293C…
- OncoKB ↗www.oncokb.org/gene/TP53/P98R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121568003
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1444043)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.955. BayesDel score = 0.591769.
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; COSV113304063, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.