About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.524G>A, p.(Arg175His)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
R175H is assigned PS3 (Strong) in the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3). The variant is non-functional in the Kato et al. (PMID:12826609) comprehensive functional assay and demonstrates loss of function in all three other eligible assays: Giacomelli et al. (PMID:30224644), Kotler et al. (PMID:29979965), and Kawaguchi et al. (PMID:16007150). Per TP53 VCEP v2.4.0 PS3 rule: non-functional on Kato data AND LOF by the majority of other eligible assays meets PS3 (Strong).
PM1Moderate
PM1 · moderate
The variant is located at codon 175, which is explicitly listed in the TP53 VCEP v2.4.0 PM1 rule as a codons where PM1 (Moderate) applies: 'Missense variants within the following codons: 175, 245, 248, 249, 273, 282.' Additionally, COSMIC reports n=2560 somatic occurrences at this residue, exceeding the ≥10 somatic occurrences threshold for PM1_Moderate via cancerhotspots.org.
PM2Supporting
PM2 · supporting
The variant is present at extremely low frequency in gnomAD. In v4.1, overall AF = 4.34e-06 (7/1,614,062 alleles, 0.000434%), which is below the VCEP PM2_Supporting threshold of <0.003% (0.00003). The highest subpopulation frequency is European (non-Finnish) at AF = 5.93e-06 (7/1,180,032, 0.000593%), also below the <0.004% (0.00004) subpopulation threshold. In v2.1, only 1 allele was observed (1/251,276, AF = 3.98e-06). The variant is absent from gnomAD-Canada v1.0. Per VCEP PM2_Supporting rules, these frequencies meet the PM2_Supporting criterion.
PP3Supporting
PP3 · supporting
The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3 to c.524G>A. The variant has aGVGD Class C25 and BayesDel score 0.54619 (≥0.16), meeting the VCEP PP3_Supporting rule: 'aGVGD class C25-C55 and BayesDel score ≥0.16.' SpliceAI max delta = 0.01, indicating no predicted splicing effect. REVEL score = 0.922 (deleterious).
PP5Supporting
PP5 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM1 moderate (+2) + PM2 supporting (+1) + PP3 supporting (+1) + PP5 supporting (+1) = 9 points, which maps to Likely Pathogenic.
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
7 / 1,614,062 alleles
gnomAD v4.1: 7 / 1,614,062 alleles. Recorded AF 4.33688e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97969e-06; MAF= 0.00040%, 1/251276 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80282e-06; MAF= 0.00088%, 1/113600 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
31 reported laboratory submissions
31 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
2560 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52661038, n = 2560 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.
26 criteria with recorded statuses: 5 met · 4 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PS3 (Strong): R175H is non-functional in the Kato et al. systematic functional assay and demonstrates loss of function in all three other eligible VCEP assays (Giacomelli, Kotler, Kawaguchi). This meets the TP53 VCEP v2.4.0 PS3 rule: non-functional on Kato data AND LOF by the majority of other eligible assays.
PM1 (Moderate): The variant is located at codon 175, which is explicitly listed in the TP53 VCEP PM1 criteria as a codon where PM1 (Moderate) applies. COSMIC reports 2,560 somatic occurrences at this residue.
PM2 (Supporting): The variant is extremely rare in population databases. gnomAD v4.1 reports an allele frequency of 4.34e-06 (7/1,614,062 alleles), well below the VCEP PM2_Supporting threshold of <0.003%. The highest subpopulation frequency (European non-Finnish) is 5.93e-06, below the <0.004% subpopulation threshold.
PP3 (Supporting): The VCEP PP3-BP4-codes.xlsx assigns PP3 to c.524G>A. The variant has aGVGD Class C25 and BayesDel score 0.54619 (≥0.16), meeting the VCEP PP3_Supporting rule. SpliceAI predicts no splicing impact (max delta = 0.01).
PS4, PM5, PP1, and PS2 were not assessed due to absent or incomplete proband-level data in the evidence package; the VCEP expert panel's Pathogenic classification on ClinVar suggests these criteria may contribute additional points in the full VCEP curation. The expert panel classification in ClinVar as Pathogenic (ClinVar ID 12374) is noted but the VCEP does not permit PP5 for independent criterion application.
Based on assessable evidence, four criteria are met: PS3 (Strong, +4 points), PM1 (Moderate, +2 points), PM2 (Supporting, +1 point), PP3 (Supporting, +1 point). Total = 8 points. Under the Tavtigian point-based framework adopted by the TP53 VCEP v2.4.0, 8 points falls in the 6-9 range → Likely Pathogenic. The ClinGen TP53 VCEP expert panel has independently classified this variant as Pathogenic on ClinVar, which likely incorporates additional evidence (PS4, PM5, PP1) beyond what is available in the current evidence package.
No criteria match.
Met · 5
PS3 StrongR175H is assigned PS3 (Strong) in the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3). The variant is non-functional in the Kato et al. (PMID:12826609) comprehensive functional assay and demonstrates loss of function in all three other eligible assays: Giacomelli et al. (PMID:30224644), Kotler et al. (PMID:29979965), and Kawaguchi et al. (PMID:16007150). Per TP53 VCEP v2.4.0 PS3 rule: non-functional on Kato data AND LOF by the majority of other eligible assays meets PS3 (Strong). Details ▾Hide ▴
Evidence considered
- Functional-worksheet.xlsx: R175H = Non-functional (Kato)
- LOF (Giacomelli)
- LOF (Kotler)
- LOF (Kawaguchi)
- VCEP-assigned PS3. PMID:15781620 reports R175H as a loss-of-function control with DsubG1 = 2.7 vs WT 8.4.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:15781620 ↗cspec ↗1282660915781620
PM1 ModerateThe variant is located at codon 175, which is explicitly listed in the TP53 VCEP v2.4.0 PM1 rule as a codons where PM1 (Moderate) applies: 'Missense variants within the following codons: 175, 245, 248, 249, 273, 282.' Additionally, COSMIC reports n=2560 somatic occurrences at this residue, exceeding the ≥10 somatic occurrences threshold for PM1_Moderate via cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- Codon 175 is explicitly listed in VCEP PM1 criteria. COSMIC: 2560 somatic occurrences. Variant lies in a statistically significant hotspot (cancerhotspots.org).
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codes
PM2 SupportingThe variant is present at extremely low frequency in gnomAD. In v4.1, overall AF = 4.34e-06 (7/1,614,062 alleles, 0.000434%), which is below the VCEP PM2_Supporting threshold of <0.003% (0.00003). The highest subpopulation frequency is European (non-Finnish) at AF = 5.93e-06 (7/1,180,032, 0.000593%), also below the <0.004% (0.00004) subpopulation threshold. In v2.1, only 1 allele was observed (1/251,276, AF = 3.98e-06). The variant is absent from gnomAD-Canada v1.0. Per VCEP PM2_Supporting rules, these frequencies meet the PM2_Supporting criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=4.34e-06 (7/1
- 614
- 062)
- gnomAD v2.1: AF=3.98e-06 (1/251
- 276)
- grpmax FAF=2.47e-06. All well below VCEP PM2_Supporting thresholds. Absent from gnomAD-Canada v1.0.
Sources
PP3 SupportingThe TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3 to c.524G>A. The variant has aGVGD Class C25 and BayesDel score 0.54619 (≥0.16), meeting the VCEP PP3_Supporting rule: 'aGVGD class C25-C55 and BayesDel score ≥0.16.' SpliceAI max delta = 0.01, indicating no predicted splicing effect. REVEL score = 0.922 (deleterious). Details ▾Hide ▴
Evidence considered
- PP3-BP4-codes.xlsx: c.524G>A assigned PP3. aGVGD Class C25
- BayesDel 0.54619 (≥0.16). REVEL 0.922. SpliceAI max delta 0.01 (no splicing effect).
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7revelbayesdelspliceai ↗cspec ↗
Not met · 4 · evaluated, threshold not reached
BA1 The TP53 VCEP BA1 rule requires filtering allele frequency (FAF) ≥0.001 (0.1%) in a single gnomAD continental subpopulation (excluding founder populations) with ≥2,000 alleles and ≥2 alleles present. The gnomAD v4.1 grpmax FAF = 2.47e-06, which is several orders of magnitude below the BA1 threshold. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 2.47e-06
- well below BA1 threshold of ≥0.001. gnomAD v2.1: 1/251
- 276 alleles.
Sources
BS1 The TP53 VCEP BS1 rule requires filtering allele frequency (FAF) ≥0.0003 (0.03%) but <0.001 in a single gnomAD continental subpopulation (excluding founder populations) with ≥2,000 alleles and ≥2 alleles present. The gnomAD v4.1 grpmax FAF = 2.47e-06 is below the 0.0003 threshold. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 2.47e-06
- below BS1 threshold of ≥0.0003. gnomAD v2.1: 1/251
- 276 alleles.
Sources
BS3 The TP53 VCEP Functional-worksheet.xlsx assigns PS3 (not BS3) to R175H. The variant is non-functional in the Kato assay and shows loss of function in all eligible assays (Giacomelli, Kotler, Kawaguchi). BS3 requires functional (BS3_Strong) or partially functional (BS3_Supporting) outcomes on Kato data with no LOF on other assays. R175H is the opposite of BS3: it demonstrates complete loss of function across all assay platforms. Details ▾Hide ▴
Evidence considered
- Functional-worksheet.xlsx: R175H = PS3. Non-functional on Kato
- LOF on all other assays. No evidence of normal or partial function.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codescspec ↗1282660915781620
BP4 The TP53 VCEP PP3-BP4-codes.xlsx assigns PP3 (not BP4) to c.524G>A. BP4_Moderate requires BayesDel ≤ -0.008, and BP4_Supporting requires BayesDel <0.16 and >-0.008. The variant's BayesDel score is 0.54619, which is far above both BP4 thresholds and falls within the PP3 range. SpliceAI max delta = 0.01, confirming no predicted splicing effect, but this alone is insufficient for BP4 when in silico scores are strongly pathogenic. BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel = 0.54619 (far above BP4 thresholds of ≤ -0.008 or <0.16). REVEL = 0.922. SpliceAI = 0.01. VCEP PP3-BP4-codes assigns PP3
- not BP4.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revelcspec ↗
Not assessed · 8 · no assessment recorded
PS2 No de novo data are available in the evidence package. The TP53 VCEP PS2 rule requires proband-level LFS cancer type point scoring using the Table of LFS Cancers and Points for PS2 and PP1 Code Application; no proband data with cancer phenotypes were provided for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations or proband cancer phenotype data available in the evidence package.
Still missing
- De novo observations or proband-level LFS cancer data are needed to assess PS2.
Sources
vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 The TP53 VCEP PS4 rule requires proband-level point scoring based on strongly associated (4 pts) and moderately associated (2 pts) LFS cancers using the PS4-Points-Table. While ClinVar reports 31 clinical laboratories classifying this variant as Pathogenic and the VCEP expert panel classifies it as Pathogenic, the evidence package does not contain the individual proband cancer phenotype data required to compute PS4 points. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic by expert panel (31 clinical labs). Expert panel classification implies PS4 points were scored
- but individual proband data are not available in the evidence package for independent computation.
Still missing
- Individual proband cancer phenotype data with LFS cancer types are needed to compute PS4 point totals per VCEP rules.
Sources
PM5 The TP53 VCEP PM5 rule requires ≥1 (moderate) or ≥2 (strong) different missense variants at the same residue previously determined to be pathogenic according to the VCEP's specifications. Multiple missense variants exist at codon 175 (R175G, R175C, R175L, R175P, etc.), and R175G has a PS3 assignment in the Functional-worksheet (non-functional on Kato, LOF on all assays). However, full VCEP pathogenic classifications for comparator variants at codon 175 are not available in the evidence package, so PM5 cannot be independently applied. In addition, the pm5_candidates.json pipeline artifact incorrectly flagged the variant class as non-missense; the variant is a canonical missense substitution (c.524G>A, p.Arg175His). Details ▾Hide ▴
Evidence considered
- Multiple missense variants at codon 175 exist (R175G
- R175C
- R175L
- R175P
- etc.). R175G has PS3 assignment in VCEP Functional-worksheet but full VCEP classification not available.
Still missing
- Full VCEP classifications for other codon 175 missense variants (especially R175G) are needed to determine PM5 strength.
Sources
PP1 No cosegregation data are available in the evidence package. The TP53 VCEP PP1 rule requires cosegregation observed in ≥3 meioses (supporting), 5-6 meioses (moderate), or ≥7 meioses (strong) across one or more families. No family segregation data were provided. Details ▾Hide ▴
Evidence considered
- No cosegregation or family data available in the evidence package.
Still missing
- Family cosegregation data across meioses are needed to assess PP1.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 The TP53 VCEP PP4 rule requires observation of the variant with variant allele fraction (VAF) 5-35%. No patient-specific VAF data are available in the evidence package. While the variant is well-established as a germline pathogenic variant in Li-Fraumeni syndrome, individual proband phenotype and VAF data were not provided for PP4 scoring. Details ▾Hide ▴
BS2 The TP53 VCEP BS2 rule requires ≥2 (supporting), 4-7 (moderate), or ≥8 (strong) unrelated females who have reached at least 60 years of age without cancer, all from a single source. No data on healthy elderly female carriers are available in the evidence package. Details ▾Hide ▴
Evidence considered
- No data on healthy elderly female carriers available in the evidence package.
Still missing
- Data on unrelated females ≥60 years without cancer who carry this variant are needed to assess BS2.
Sources
BS4 No segregation data are available in the evidence package. The TP53 VCEP BS4 rule requires lack of segregation in affected family members diagnosed with LFS-associated cancers. No family segregation studies were provided. Details ▾Hide ▴
Evidence considered
- No family segregation data available in the evidence package.
Still missing
- Family segregation data (lack of segregation in affected members) are needed to assess BS4.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS5 PS5 requires a different missense variant at the same nucleotide position (c.524) that has been established as pathogenic by the TP53 VCEP. The PP3-BP4-codes.xlsx identifies c.524G>T (p.Arg175Leu) and c.524G>C (p.Arg175Pro) at this position with PP3_moderate assignments, but full VCEP pathogenic classifications for these comparator variants are not available in the evidence package. Without confirmed VCEP pathogenic classification of a comparator, PS5 cannot be applied. Details ▾Hide ▴
Evidence considered
- c.524G>T (p.Arg175Leu) and c.524G>C (p.Arg175Pro) exist at the same nucleotide position with PP3_moderate assignments
- but lack confirmed VCEP P/LP classifications.
Still missing
- Full VCEP classifications for c.524G>T and c.524G>C are needed to determine PS5 eligibility.
Sources
vcep_pp3_bp4_codespm5_candidates
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. This variant (c.524G>A, p.Arg175His) is a missense substitution and does not fall into the null-variant categories of nonsense, frameshift, canonical splice site (+/-1,2), initiation codon, or exon-level deletion covered by the TP53 VCEP PVS1 flowchart. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant. PVS1 gene gate is eligible (TP53 LOF mechanism established) but the variant class does not meet PVS1 criteria.
Sources
pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_flowchart
PS1 N/APS1 requires a different nucleotide change producing the same amino acid change as a previously established pathogenic variant. The only nucleotide change that produces p.Arg175His (R175H) is c.524G>A; no alternative nucleotide substitution at this codon yields the same histidine substitution. There is no comparator variant for PS1. Details ▾Hide ▴
Evidence considered
- Arg175His (R175H) can only be produced by c.524G>A. No alternative nucleotide change at codon 175 produces histidine.
Sources
PM6 VCEPPM6 is marked as 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion is not for use under this gene-specific framework. Details ▾Hide ▴
PP2 VCEPPP2 is marked as 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion (missense variant in a gene with low rate of benign missense variation) is not used under this gene-specific framework. Details ▾Hide ▴
BP1 VCEPBP1 is marked as 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion (missense variant in a gene where primarily truncating variants cause disease) is not used under this gene-specific framework. Details ▾Hide ▴
BP2 VCEPBP2 is marked as 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion (observed in trans with a pathogenic variant in a recessive disorder) is not used under this gene-specific framework. Details ▾Hide ▴
BP5 VCEPBP5 is marked as 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion (variant found in a case with an alternate molecular basis for disease) is not used under this gene-specific framework. Details ▾Hide ▴
BP6 VCEPBP6 is marked as 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion (reputable source reports variant as benign) is not used under this gene-specific framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) or intronic variants with no predicted splicing impact. This variant (c.524G>A) is a missense substitution (p.Arg175His), not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous or intronic. BP7 not applicable.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.524G>A
- Protein (HGVS p.)
- NP_000537.3:p.(Arg175His)
- GRCh38
- chr17:7675088 C>T
- GRCh37
- chr17:7578406 C>T
- ClinVar
- 951578, 12374, 4189264, 376649, 245851, 182963
- COSMIC
- COSV52661038
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
7 / 1,614,062 alleles
AF 4.34e-06 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1
1 / 251,276 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 7 / 1,614,062 alleles · 0 hom · FAF 2.5e-06
| European (non-Finnish)7 / 1,180,032 | 5.9e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,276 alleles · 0 hom
| European (non-Finnish)1 / 113,600 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.33688e-06; MAF= 0.00043%, 7/1614062 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93204e-06; MAF= 0.00059%, 7/1180032 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97969e-06; MAF= 0.00040%, 1/251276 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80282e-06; MAF= 0.00088%, 1/113600 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.922
- BayesDel
- 0.546
How the predictions were used
PP3 SupportingThe TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3 to c.524G>A. The variant has aGVGD Class C25 and BayesDel score 0.54619 (≥0.16), meeting the VCEP PP3_Supporting rule: 'aGVGD class C25-C55 and BayesDel score ≥0.16.' SpliceAI max delta = 0.01, indicating no predicted splicing effect. REVEL score = 0.922 (deleterious). Details ▾Hide ▴
Evidence considered
- PP3-BP4-codes.xlsx: c.524G>A assigned PP3. aGVGD Class C25
- BayesDel 0.54619 (≥0.16). REVEL 0.922. SpliceAI max delta 0.01 (no splicing effect).
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7revelbayesdelspliceai ↗cspec ↗
BP4 The TP53 VCEP PP3-BP4-codes.xlsx assigns PP3 (not BP4) to c.524G>A. BP4_Moderate requires BayesDel ≤ -0.008, and BP4_Supporting requires BayesDel <0.16 and >-0.008. The variant's BayesDel score is 0.54619, which is far above both BP4 thresholds and falls within the PP3 range. SpliceAI max delta = 0.01, confirming no predicted splicing effect, but this alone is insufficient for BP4 when in silico scores are strongly pathogenic. BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel = 0.54619 (far above BP4 thresholds of ≤ -0.008 or <0.16). REVEL = 0.922. SpliceAI = 0.01. VCEP PP3-BP4-codes assigns PP3
- not BP4.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revelcspec ↗
BP7 N/ABP7 applies to synonymous (silent) or intronic variants with no predicted splicing impact. This variant (c.524G>A) is a missense substitution (p.Arg175His), not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous or intronic. BP7 not applicable.
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 = 0.01). REVEL score = 0.922. BayesDel score = 0.54619.
9 paper records listed. 2 cited in the classification.
Cited in the classification
-
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. · 2003 Jul 8R175H was assessed in a high-resolution comprehensive missense mutation functional analysis across the entire p53 coding sequence. The variant was classified as non-functional, with complete loss of transcriptional activity across p53 target gene reporters in yeast-based and mammalian assays.→ PS3 Names this variant
-
PMID 15781620 ↗Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s.R175H was used as a loss-of-function control in a study of 179 diverse mutant p53s. The variant had a DsubG1 of 2.7 ± 1.9 versus 8.4 ± 3.3 for wild-type p53, confirming severely impaired apoptotic induction in Saos-2 cells.→ PS3 Names this variant
Source detail
The DsubG1 of R175H, a loss-of-function mutation, was 2.7 ± 1.9.
Location Results, 'The Ability to Induce Apoptosis among the Selected Diverse Mutant p53s'; Figures 1–3
Context Saos-2 human osteosarcoma cells; transient transfection of p53 expression vectors; FACS-based subG1 apoptosis assay (DsubG1)
Other recorded publications
-
PMID 10713666 ↗Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.No paper-specific finding is recorded.
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PMID 21445056 ↗Gain of function of mutant p53 by coaggregation with multiple tumor suppressors.No paper-specific finding is recorded.
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PMID 25584008 ↗Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study.No paper-specific finding is recorded.
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PMID 31068365 ↗A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1.No paper-specific finding is recorded.
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PMID 12007217 ↗The IARC TP53 database: new online mutation analysis and recommendations to users.Olivier M et al. · 2002No paper-specific finding is recorded.
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PMID 12619118 ↗Germline TP53 mutations and Li-Fraumeni syndrome.Varley JM · 2003No paper-specific finding is recorded.
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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
7 / 1,614,062 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
31 Pathogenic
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/12374/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578406-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675088-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.524G…
- OncoKB ↗www.oncokb.org/gene/TP53/R175H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121482789
- 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= 4.33688e-06; MAF= 0.00043%, 7/1614062 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93204e-06; MAF= 0.00059%, 7/1180032 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97969e-06; MAF= 0.00040%, 1/251276 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80282e-06; MAF= 0.00088%, 1/113600 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 12374)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.922. BayesDel score = 0.54619.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52661038, n = 2560 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.