About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.319T>C, p.(Tyr107His)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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.
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BS1Strong
BS1 · strong
This variant meets TP53 BS1 because its filtering allele frequency is above the BS1 threshold of 0.0003 but below the BA1 threshold of 0.001. The highest observed grpmax FAF is 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1, with the highest population frequency in African/African American individuals.
BS3Supporting
BS3 · supporting
Published TP53 functional evidence supports BS3_Supporting for this variant. In the TP53 functional worksheet, Y107H is listed as partially functional with no loss of function in other eligible assay columns, and the pre-assigned TP53 VCEP code is BS3_Supporting.
BP4Supporting
BP4 · supporting
Computational evidence supports TP53 BP4. The TP53 VCEP in silico worksheet assigns BP4 for c.319T>C, the BayesDel score is 0.020196, which is below the TP53 PP3 threshold of 0.16 and above the BP4_Moderate cutoff of -0.008, and SpliceAI predicts no splice effect with a max delta score of 0.00.
BP6Supporting
BP6 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
TP53 ClinGen VCEP v2.4.0 Tavtigian point-based final-classification 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
90 / 1,612,522 alleles
gnomAD v4.1: 90 / 1,612,522 alleles. Recorded AF 5.58132e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000120254; MAF= 0.01203%, 34/282734 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112233; MAF= 0.11223%, 28/24948 alleles, homozygotes = 0); grpmax FAF= 0.00079507.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
15 reported laboratory submissions
10 Likely benign · 3 Benign · 2 Uncertain significance.
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.
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53179040, n = 2 times).
Cancer Hotspots
This variant lies 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.
28 criteria with recorded statuses: 4 met · 6 not met · 7 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
The TP53 c.319T>C (p.Tyr107His) variant has been observed in somatic cancers with 2 COSMIC observations and has been reported in ClinVar with a Benign expert-panel classification from the ClinGen TP53 Variant Curation Expert Panel.
This variant is present in gnomAD above the TP53 PM2 threshold and within the TP53 BS1 range, with grpmax filtering allele frequencies of 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1.
In the TP53 VCEP functional worksheet, Y107H is recorded as partially functional with no loss of function in other eligible assay columns, supporting BS3_Supporting and arguing against PS3.
TP53-specific in silico assessment assigns BP4 for c.319T>C; BayesDel is 0.020196, SpliceAI predicts no splice impact with a max delta score of 0.00, and the available computational evidence does not support PP3.
No criteria match.
Met · 4
BS1 StrongThis variant meets TP53 BS1 because its filtering allele frequency is above the BS1 threshold of 0.0003 but below the BA1 threshold of 0.001. The highest observed grpmax FAF is 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1, with the highest population frequency in African/African American individuals. Details ▾Hide ▴
Rule
TP53 BS1 applies when FAF is at or above 0.0003 and below 0.001 in an eligible ancestry group.
Evidence considered
- gnomAD v2 grpmax FAF 0.00079507
- African/African American AF 0.00112233
- gnomAD v4 grpmax FAF 0.00079357
- African/African American AF 0.000973411
Sources
BS3 SupportingPublished TP53 functional evidence supports BS3_Supporting for this variant. In the TP53 functional worksheet, Y107H is listed as partially functional with no loss of function in other eligible assay columns, and the pre-assigned TP53 VCEP code is BS3_Supporting. Details ▾Hide ▴
Rule
TP53 BS3_Supporting applies to partially functional Kato data with no evidence of loss of function across available assays.
Evidence considered
- Functional worksheet pre-assigned code BS3_Supporting
- Assay summary recorded as partially functional and noLOF
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗
BP4 SupportingComputational evidence supports TP53 BP4. The TP53 VCEP in silico worksheet assigns BP4 for c.319T>C, the BayesDel score is 0.020196, which is below the TP53 PP3 threshold of 0.16 and above the BP4_Moderate cutoff of -0.008, and SpliceAI predicts no splice effect with a max delta score of 0.00. Details ▾Hide ▴
Rule
TP53 BP4_Supporting applies to missense variants with BayesDel below 0.16 and no predicted splice effect.
Evidence considered
- Precomputed TP53 VCEP code: BP4
- PP3-BP4 worksheet row: c.319T>C | p.Tyr107His | Class C0 | 0.020196 | BP4 | 0.04
- SpliceAI max delta score 0.00
- REVEL score 0.569
Sources
Not met · 6 · evaluated, threshold not reached
PS3 TP53 functional evidence does not support a damaging loss-of-function interpretation for this variant. In the TP53 functional worksheet, Y107H is recorded as partially functional with no loss of function in other eligible assay columns and is assigned BS3_Supporting rather than a PS3 code. Details ▾Hide ▴
Rule
TP53 PS3 requires non-functional or loss-of-function assay patterns; those were not present.
Evidence considered
- Functional worksheet row: Y107H | Partially functional | noLOF | noLOF | BS3_Supporting
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗
PS4 Available evidence does not support PS4. This variant does not meet the TP53 PM2_Supporting rarity prerequisite because it is present in gnomAD above the PM2 threshold, and no qualifying Li-Fraumeni syndrome point-based case enrichment data were identified. Details ▾Hide ▴
Rule
TP53 PS4 requires PM2_Supporting first and then point-based case evidence.
Evidence considered
- gnomAD v4 total AF 0.0000558
- African/African American AF 0.000973
- gnomAD v2 total AF 0.000120
- African/African American AF 0.001122
Still missing
- No qualifying TP53 PS4 point count was identified from independent affected probands
Sources
PM1 Available evidence does not support PM1. Codon 107 is not one of the TP53 codons specified for automatic PM1 application, Cancer Hotspots evidence for this residue was uncertain, and only 2 somatic observations were identified in COSMIC, which does not establish a TP53 hotspot-based PM1 determination. Details ▾Hide ▴
Rule
TP53 PM1 is reserved for specified hotspot codons or qualifying Cancer Hotspots recurrence.
Evidence considered
- TP53 codon 107 is not among codons 175
- 245
- 248
- 249
- 273
- 282
- COSMIC somatic count 2
- Cancer Hotspots flagged as uncertain and requiring human review
Sources
PM2 This variant is too common for TP53 PM2_Supporting. Its total allele frequency is 0.000120 in gnomAD v2.1 and 0.0000558 in gnomAD v4.1, both above the TP53 PM2 threshold of less than 0.00003, and multiple African/African American alleles are present above the single-group threshold of less than 0.00004. Details ▾Hide ▴
Rule
TP53 PM2_Supporting requires AF less than 0.00003 and, when multiple alleles are present in one group, group AF less than 0.00004.
Evidence considered
- gnomAD v2 total AF 0.000120254
- African/African American AF 0.00112233
- gnomAD v4 total AF 0.0000558132
- African/African American AF 0.000973411
Sources
PP3 Computational evidence does not support PP3 for this TP53 missense variant. The TP53 VCEP in silico worksheet assigns BP4, not PP3, with BayesDel score 0.020196 below the TP53 PP3 threshold of 0.16 and SpliceAI max delta score 0.00 showing no predicted splice effect. Details ▾Hide ▴
Rule
TP53 PP3 for missense variants requires qualifying aGVGD class and BayesDel score at or above 0.16, or qualifying splice prediction.
Evidence considered
- Precomputed TP53 VCEP code: BP4
- BayesDel score 0.020196
- SpliceAI max delta score 0.00
- REVEL score 0.569
Sources
BA1 This variant does not meet TP53 BA1 because the observed filtering allele frequency does not reach the BA1 threshold of 0.001. The highest observed grpmax FAF is 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1. Details ▾Hide ▴
Rule
TP53 BA1 requires FAF at or above 0.001.
Evidence considered
- gnomAD v2 grpmax FAF 0.00079507
- gnomAD v4 grpmax FAF 0.00079357
Sources
Not assessed · 7 · no assessment recorded
PS1 No same-amino-acid pathogenic TP53 comparator was confirmed for this codon, so PS1 was not assessed. Details ▾Hide ▴
Rule
PS1 requires a previously established same amino acid change.
Evidence considered
- TP53 VCEP PS1 requires a different nucleotide change causing the same amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic assertion
Still missing
- A direct same-amino-acid comparator search was not verified.
Sources
PS2 No confirmed de novo observation with the TP53-specific clinical details and parental confirmation required for PS2 was identified. Details ▾Hide ▴
Rule
TP53 PS2 is point based and requires confirmed de novo evidence.
Evidence considered
- No de novo case evidence was assembled
Still missing
- No parental testing or maternity/paternity confirmation was identified
- No qualifying Li-Fraumeni syndrome point-based de novo evidence was identified
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PM5 PM5 was not assessed because no verified same-residue TP53 pathogenic or likely pathogenic comparator set was confirmed for codon 107 in the reviewed materials. Details ▾Hide ▴
Rule
TP53 PM5 is classic same-residue missense logic.
Evidence considered
- TP53 PM5 requires previously established pathogenic or likely pathogenic missense variants at the same residue
Still missing
- No validated same-residue TP53 VCEP comparator variants were confirmed for codon 107
Sources
cspec ↗pm5_candidates
PP1 No segregation data were identified to show co-segregation of this variant with Li-Fraumeni syndrome-associated disease across informative meioses. Details ▾Hide ▴
Rule
TP53 PP1 requires 3 or more informative meioses, depending on strength.
Evidence considered
- No segregation dataset was assembled
Still missing
- No informative pedigree or meiosis count was identified
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No qualifying low-variant-allele-fraction constitutional mosaic observations were identified for this variant, so TP53-specific PP4 was not assessed. Details ▾Hide ▴
Rule
TP53 PP4 requires qualifying low-VAF observations.
Evidence considered
- TP53 PP4 is a mosaicism-focused criterion
Still missing
- No case-level blood variant allele fraction observations were identified
Sources
BS2 No single-source dataset of unaffected older female carriers was identified to support BS2. Details ▾Hide ▴
Rule
TP53 BS2 is based on unaffected older female carriers from one source.
Evidence considered
- TP53 BS2 requires age- and sex-specific unaffected carrier counts from a single source
Still missing
- No qualifying unaffected female carrier series from one source was identified
Sources
BS4 No family data were identified to demonstrate lack of segregation with Li-Fraumeni syndrome-associated disease. Details ▾Hide ▴
Rule
TP53 BS4 requires lack of segregation in affected relatives.
Evidence considered
- No non-segregation dataset was assembled
Still missing
- No informative non-segregation pedigree was identified
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, TP53 p.(Tyr107His), and does not fall into the TP53 null-variant categories used for PVS1. Available splice evidence does not support a loss-of-function splicing mechanism, with SpliceAI max delta score 0.00. Details ▾Hide ▴
Rule
TP53 PVS1 applies to null or qualifying splice variants, not this missense change.
Evidence considered
- Missense consequence p.(Tyr107His)
- Generic PVS1 scaffold marked this variant outside nonsense/frameshift/canonical splice buckets
- SpliceAI max delta score 0.00
Sources
PM3 VCEPPM3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PM4 VCEPPM4 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PM6 VCEPPM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable in this framework. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP5 VCEPBP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
TP53 BP7 applies to synonymous or qualifying intronic variants.
Evidence considered
- Variant consequence p.(Tyr107His)
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.319T>C
- Protein (HGVS p.)
- NP_000537.3:p.(Tyr107His)
- GRCh38
- chr17:7676050 A>G
- GRCh37
- chr17:7579368 A>G
- ClinVar
- 4800656, 140786
- COSMIC
- COSV53179040
Gene diagram
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
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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
90 / 1,612,522 alleles
AF 5.58e-05 · 0 homozygotes · FAF 0.000794
gnomAD v2.1
34 / 282,734 alleles
AF 0.00012 · 0 homozygotes · FAF 0.000795
By genetic ancestry
gnomAD v4.1
AF 5.6e-05 · 90 / 1,612,522 alleles · 0 hom · FAF 0.00079
| African/African American73 / 74,994 | 0.00097 |
| Remaining individuals10 / 62,354 | 0.00016 |
| Admixed American7 / 60,016 | 0.00012 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 0.00012 · 34 / 282,734 alleles · 0 hom · FAF 0.0008
| African/African American28 / 24,948 | 0.0011 |
| Admixed American6 / 35,434 | 0.00017 |
0 alternate alleles recorded in 6 other groups: Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.58132e-05; MAF= 0.00558%, 90/1612522 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000973411; MAF= 0.09734%, 73/74994 alleles, homozygotes = 0); grpmax FAF= 0.00079357.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000120254; MAF= 0.01203%, 34/282734 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112233; MAF= 0.11223%, 28/24948 alleles, homozygotes = 0); grpmax FAF= 0.00079507.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.569
- BayesDel
- 0.020
How the predictions were used
BP4 SupportingComputational evidence supports TP53 BP4. The TP53 VCEP in silico worksheet assigns BP4 for c.319T>C, the BayesDel score is 0.020196, which is below the TP53 PP3 threshold of 0.16 and above the BP4_Moderate cutoff of -0.008, and SpliceAI predicts no splice effect with a max delta score of 0.00. Details ▾Hide ▴
Rule
TP53 BP4_Supporting applies to missense variants with BayesDel below 0.16 and no predicted splice effect.
Evidence considered
- Precomputed TP53 VCEP code: BP4
- PP3-BP4 worksheet row: c.319T>C | p.Tyr107His | Class C0 | 0.020196 | BP4 | 0.04
- SpliceAI max delta score 0.00
- REVEL score 0.569
Sources
PP3 Computational evidence does not support PP3 for this TP53 missense variant. The TP53 VCEP in silico worksheet assigns BP4, not PP3, with BayesDel score 0.020196 below the TP53 PP3 threshold of 0.16 and SpliceAI max delta score 0.00 showing no predicted splice effect. Details ▾Hide ▴
Rule
TP53 PP3 for missense variants requires qualifying aGVGD class and BayesDel score at or above 0.16, or qualifying splice prediction.
Evidence considered
- Precomputed TP53 VCEP code: BP4
- BayesDel score 0.020196
- SpliceAI max delta score 0.00
- REVEL score 0.569
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
TP53 BP7 applies to synonymous or qualifying intronic variants.
Evidence considered
- Variant consequence p.(Tyr107His)
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.569. BayesDel score = 0.020196.
6 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.No paper-specific finding is recorded.
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PMID 30224644 ↗Mutational processes shape the landscape of TP53 mutations in human cancer.No paper-specific finding is recorded.
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PMID 16061860 ↗FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.No paper-specific finding is recorded.
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PMID 27328919 ↗TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
90 / 1,612,522 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
10 Likely benign · 3 Benign · 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/140786/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579368-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7676050-A-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.319T…
- OncoKB ↗www.oncokb.org/gene/TP53/Y107H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122079772
- 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
This variant is present in gnomAD v4.1 (AF= 5.58132e-05; MAF= 0.00558%, 90/1612522 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000973411; MAF= 0.09734%, 73/74994 alleles, homozygotes = 0); grpmax FAF= 0.00079357.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000120254; MAF= 0.01203%, 34/282734 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112233; MAF= 0.11223%, 28/24948 alleles, homozygotes = 0); grpmax FAF= 0.00079507.
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 140786)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.569. BayesDel score = 0.020196.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53179040, n = 2 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.