TP53c.833C>GLikely pathogenic

Print report

Variant interpretation report

TP53 c.833C>G, p.(Pro278Arg)

NM_000546.5:c.833C>G NP_000537.3:p.(Pro278Arg) View identifiers

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.

About TP53

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 2 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0
Other laboratories (ClinVar): 3 Uncertain significance · 1 Likely pathogenic · 1 Pathogenic
Pipeline record: 6 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): PS3 (Strong) is met per the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3). The p.Pro278Arg (P278R) substitution is classified as Non-functional in the Kato et al. (PMID:12826609) assay AND demonstrates loss of function (LOF) by the majority of other eligible functional assays (Giacomelli: LOF, Kotler: LOF, Funk: noLOF). Two of three non-Kato assays show LOF, satisfying the VCEP rule for PS3: 'Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.'
PM1 (moderate): PM1 (Moderate) is met per the TP53 VCEP specifications. Although codon 278 is not among the listed major hotspot codons (175, 245, 248, 249, 273, 282), the variant is a germline missense change at a residue that is a statistically significant hotspot in cancerhotspots.org, and the exact amino acid change (Pro278Arg) has 82 somatic occurrences in COSMIC (COSV52661225), well exceeding the VCEP threshold of >=10 somatic occurrences for the same amino acid change.
PM2 (supporting): PM2_Supporting is met per the TP53 VCEP population frequency rules. The variant is absent from gnomAD v2.1 and has an allele frequency of 6.2e-7 (1/1,614,022 alleles) in gnomAD v4.1, with the highest subpopulation frequency of 8.5e-7 in European (non-Finnish) (1/1,180,014 alleles). Both the total allele frequency (<0.00003) and the single-ancestry-group frequency with only one allele observed (<0.00004) satisfy the PM2_Supporting threshold.
PP3 (moderate): PP3_Moderate is met per the TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2), which pre-assigns PP3_moderate to c.833C>G (p.Pro278Arg). The variant has an aGVGD class of C65 and a BayesDel score of 0.607821 (>=0.16), satisfying the VCEP rule for PP3_Moderate. SpliceAI predicts no splicing impact (max delta = 0.00), so no splicing adjustment is needed.

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: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PS3Strong

PS3 · strong

PS3 (Strong) is met per the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3). The p.Pro278Arg (P278R) substitution is classified as Non-functional in the Kato et al. (PMID:12826609) assay AND demonstrates loss of function (LOF) by the majority of other eligible functional assays (Giacomelli: LOF, Kotler: LOF, Funk: noLOF). Two of three non-Kato assays show LOF, satisfying the VCEP rule for PS3: 'Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.'

PM1Moderate

PM1 · moderate

PM1 (Moderate) is met per the TP53 VCEP specifications. Although codon 278 is not among the listed major hotspot codons (175, 245, 248, 249, 273, 282), the variant is a germline missense change at a residue that is a statistically significant hotspot in cancerhotspots.org, and the exact amino acid change (Pro278Arg) has 82 somatic occurrences in COSMIC (COSV52661225), well exceeding the VCEP threshold of >=10 somatic occurrences for the same amino acid change.

PM2Supporting

PM2 · supporting

PM2_Supporting is met per the TP53 VCEP population frequency rules. The variant is absent from gnomAD v2.1 and has an allele frequency of 6.2e-7 (1/1,614,022 alleles) in gnomAD v4.1, with the highest subpopulation frequency of 8.5e-7 in European (non-Finnish) (1/1,180,014 alleles). Both the total allele frequency (<0.00003) and the single-ancestry-group frequency with only one allele observed (<0.00004) satisfy the PM2_Supporting threshold.

PP3Moderate

PP3 · moderate

PP3_Moderate is met per the TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2), which pre-assigns PP3_moderate to c.833C>G (p.Pro278Arg). The variant has an aGVGD class of C65 and a BayesDel score of 0.607821 (>=0.16), satisfying the VCEP rule for PP3_Moderate. SpliceAI predicts no splicing impact (max delta = 0.00), so no splicing adjustment is needed.

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 moderate (+2) = 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

1 / 1,614,022 alleles

gnomAD v4.1: 1 / 1,614,022 alleles. Recorded AF 6.1957e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

5 reported laboratory submissions

3 Uncertain significance · 1 Likely pathogenic · 1 Pathogenic.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

82 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52661225, n = 82 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 4 not met · 8 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000546.5:c.833C>G (p.Pro278Arg) is a missense variant in TP53 exon 8, absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.2e-7, 1/1,614,022 alleles).

PS3 (Strong) is met: the variant is Non-functional in the Kato et al. functional assay AND demonstrates loss of function by the majority of other eligible assays (Giacomelli: LOF, Kotler: LOF, Funk: noLOF), per the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3).

PM1 (Moderate) is met: codon 278 is a statistically significant hotspot residue in cancerhotspots.org, and the Pro278Arg change has 82 somatic occurrences in COSMIC, far exceeding the VCEP threshold of >=10 for PM1_Moderate.

PM2 (Supporting) is met: the variant allele frequency in gnomAD v4.1 (6.2e-7) is well below the VCEP PM2_Supporting threshold of 0.00003, with no genetic ancestry group exceeding 0.00004.

PP3 (Moderate) is met per the TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2): aGVGD class C65 with BayesDel score 0.607821 (>=0.16), and SpliceAI predicts no splicing impact (max delta 0.00).

Multiple criteria remain unassessed due to absent data: PS1 (requires VCEP classification of alternate nucleotide change c.833C>A for same amino acid P278R), PS2 (no de novo report with confirmed parentage), PS4 (germline proband counts unavailable), PM5 (formal VCEP classifications for codon 278 comparators needed), PP1 (no cosegregation data), PP4 (no VAF data), BS2 (no data on elderly unaffected carriers), and BS4 (no lack-of-segregation reports).

Applying the TP53 VCEP v2.4.0 Tavtigian point system: PS3=4 + PM1=1 + PM2_Supporting=0.5 + PP3_Moderate=1 = 6.5 points, which falls in the Likely Pathogenic range (6-9 points).

This variant has been reported in ClinVar with conflicting classifications: Uncertain significance (3 clinical laboratories), Likely pathogenic (1), and Pathogenic (1). (ClinVar Variation ID: 376644)

Met · 4

PS3 StrongPS3 (Strong) is met per the TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3). The p.Pro278Arg (P278R) substitution is classified as Non-functional in the Kato et al. (PMID:12826609) assay AND demonstrates loss of function (LOF) by the majority of other eligible functional assays (Giacomelli: LOF, Kotler: LOF, Funk: noLOF). Two of three non-Kato assays show LOF, satisfying the VCEP rule for PS3: 'Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.' Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet.xlsx pre-assigned code PS3 for P278R: Kato=Non-functional
Giacomelli=LOF
Kotler=LOF
Funk=noLOF
Kawaguchi=NA. Majority of non-Kato eligible assays (2/3) show LOF.

Sources

vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codescspec ↗12826609

PM1 ModeratePM1 (Moderate) is met per the TP53 VCEP specifications. Although codon 278 is not among the listed major hotspot codons (175, 245, 248, 249, 273, 282), the variant is a germline missense change at a residue that is a statistically significant hotspot in cancerhotspots.org, and the exact amino acid change (Pro278Arg) has 82 somatic occurrences in COSMIC (COSV52661225), well exceeding the VCEP threshold of >=10 somatic occurrences for the same amino acid change. Details ▾Hide ▴

Evidence considered

Codon 278 residue is a statistically significant hotspot
COSMIC reports 82 somatic occurrences of the exact variant (COSV52661225)
>=10 threshold for PM1_Moderate is exceeded.

Sources

cspec ↗

PM2 SupportingPM2_Supporting is met per the TP53 VCEP population frequency rules. The variant is absent from gnomAD v2.1 and has an allele frequency of 6.2e-7 (1/1,614,022 alleles) in gnomAD v4.1, with the highest subpopulation frequency of 8.5e-7 in European (non-Finnish) (1/1,180,014 alleles). Both the total allele frequency (<0.00003) and the single-ancestry-group frequency with only one allele observed (<0.00004) satisfy the PM2_Supporting threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: AF=6.2e-7 (1/1
614
022)
highest subpopulation AF=8.5e-7 (European non-Finnish
1/1
180
014)
both below VCEP PM2_Supporting thresholds.

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 ModeratePP3_Moderate is met per the TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2), which pre-assigns PP3_moderate to c.833C>G (p.Pro278Arg). The variant has an aGVGD class of C65 and a BayesDel score of 0.607821 (>=0.16), satisfying the VCEP rule for PP3_Moderate. SpliceAI predicts no splicing impact (max delta = 0.00), so no splicing adjustment is needed. Details ▾Hide ▴

Evidence considered

PP3-BP4-codes.xlsx: c.833C>G assigned PP3_moderate
aGVGD Class C65
BayesDel 0.607821 >= 0.16
SpliceAI max delta 0.00 < 0.2
no predicted splicing alteration.

Sources

vcep_pp3_bp4_codesspliceai ↗bayesdelcspec ↗

Not met · 4 · evaluated, threshold not reached

BA1 BA1 requires a filtering allele frequency (FAF) >= 0.001 (0.1%) in gnomAD continental subpopulations. The highest FAF for this variant is 8.5e-7 in European (non-Finnish), well below the BA1 threshold. BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 max FAF=8.5e-7 (European non-Finnish)
well below VCEP BA1 threshold of 0.001.

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 BS1 requires a filtering allele frequency (FAF) >= 0.0003 but < 0.001 in gnomAD continental subpopulations. The highest FAF is 8.5e-7, below the BS1 threshold. BS1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 max FAF=8.5e-7 (European non-Finnish)
below VCEP BS1 threshold of 0.0003.

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS3 BS3 requires functional evidence of no damaging effect (Functional on Kato data AND no LOF by majority of eligible assays). The TP53 VCEP Functional-worksheet.xlsx assigns PS3 to P278R (not BS3), indicating the variant is damaging: Kato class is Non-functional, and the majority of other eligible assays (Giacomelli, Kotler) show LOF. BS3 is not met. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet.xlsx assigns PS3 (not BS3) to P278R
Kato=Non-functional
majority of assays show LOF.

Sources

vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codescspec ↗

BP4 BP4 (benign in silico evidence) is not met. The TP53 VCEP PP3-BP4-codes.xlsx assigns PP3_moderate (not BP4) to c.833C>G. The BayesDel score is 0.607821, far above the BP4_Supporting threshold of <0.16 and the BP4_Moderate threshold of <=-0.008. aGVGD class is C65, which explicitly precludes BP4 application per the VCEP flowchart. Details ▾Hide ▴

Evidence considered

PP3-BP4-codes.xlsx: PP3_moderate assigned
not BP4
BayesDel 0.607821 >> -0.008
aGVGD C65 precludes BP4.

Sources

vcep_pp3_bp4_codesbayesdelcspec ↗

Not assessed · 8 · no assessment recorded

PS1 PS1 requires a different nucleotide change at the same codon that results in the same amino acid change (Pro278Arg) and has been previously classified as Pathogenic or Likely Pathogenic per the TP53 VCEP specifications. The nucleotide change c.833C>A also creates p.Pro278Arg, but there is no evidence in the available materials that c.833C>A has been formally classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. PS1 cannot be applied without this prior classification. Details ▾Hide ▴

Evidence considered

c.833C>A is an alternate nucleotide change creating p.Pro278Arg per the PP3-BP4-codes spreadsheet
no VCEP classification for c.833C>A is available.

Still missing

Requires formal TP53 VCEP classification of c.833C>A (p.Pro278Arg) as Pathogenic or Likely Pathogenic before PS1 can be applied.

Sources

cspec ↗vcep_pp3_bp4_codes

PS2 PS2 requires documented de novo occurrence with confirmed parentage in a proband with Li-Fraumeni syndrome (LFS)-associated cancers. The exploratory search identified the IARC TP53 germline database as a potential source for de novo annotations at codon 278, but no published de novo case report for c.833C>G with confirmed maternity and paternity was identified in the available materials. Without a specific de novo observation, PS2 cannot be assessed. Details ▾Hide ▴

Evidence considered

Exploratory search suggests IARC TP53 database may contain de novo entries for codon 278 variants
but no confirmed de novo report for c.833C>G was retrieved.

Still missing

No published de novo case report for c.833C>G with confirmed parentage
IARC database curation may yield data.

PS4 PS4 under the TP53 VCEP requires counting independent probands with LFS-spectrum cancers using the PS4 points table (strongly associated cancers = 4 points, moderately associated = 2 points). COSMIC reports 82 somatic occurrences of this variant, confirming it is recurrent in cancer, but germline proband counts with phenotypic data are not available in the evidence bundle. The exploratory search indicates the IARC TP53 germline database may contain proband data, but this requires manual curation beyond the available materials. Details ▾Hide ▴

Evidence considered

COSMIC: 82 somatic occurrences (COSV52661225)
IARC TP53 database may contain germline proband counts for this variant.

Still missing

Germline proband count with LFS cancer phenotypes not available
IARC database curation needed for PS4 point calculation.

Sources

vcep_ps4_points_table

PM5 PM5 (same residue, different missense change previously established as pathogenic per VCEP) could potentially be applied because multiple different missense variants at codon 278 (P278A, P278H, P278L, P278S, P278T) receive PS3 (pathogenic functional evidence) in the VCEP Functional-worksheet, suggesting they would classify as Pathogenic under the VCEP framework. However, formal VCEP final classifications for comparator variants at codon 278 are not available in the evidence bundle, preventing direct application of PM5. Details ▾Hide ▴

Evidence considered

Functional worksheet shows multiple codon 278 variants with PS3: P278A
P278H
P278L
P278S
P278T
formal VCEP classifications for comparators not available.

Still missing

Formal VCEP final classifications for codon 278 comparator missense variants needed for PM5 application.

Sources

vcep_functional_worksheetcspec ↗pm5_candidates

PP1 PP1 requires cosegregation data with specific meiotic counts across families (>=3-4 meioses for Supporting, 5-6 for Moderate, >=7 across >1 family for Strong). The exploratory search indicates the IARC TP53 database may contain segregation data for codon 278 families, but no cosegregation analysis was available in the evidence bundle. Details ▾Hide ▴

Evidence considered

Exploratory search suggests IARC TP53 database may have familial segregation data for codon 278 variants
no specific cosegregation data retrieved.

Still missing

Cosegregation data (meiotic counts in LFS families with c.833C>G) needed for PP1 assessment.

Sources

cspec ↗

PP4 PP4 requires observation of the variant at variant allele fraction (VAF) 5-35% in blood, consistent with constitutional (non-somatic) origin. No VAF data for this variant is available in the evidence bundle. Details ▾Hide ▴

Evidence considered

No VAF data available for c.833C>G.

Still missing

Variant allele fraction (VAF) data in constitutional/germline samples needed.

Sources

cspec ↗

BS2 BS2 requires >=2 unrelated females who have reached at least 60 years of age without cancer (from a single source). No such data is available in the evidence bundle. Details ▾Hide ▴

Evidence considered

No data on unaffected elderly females carrying c.833C>G.

Still missing

Need data on >=60-year-old female carriers without cancer from a single source.

Sources

cspec ↗

BS4 BS4 requires lack of segregation in affected family members (i.e., family members diagnosed with LFS-associated cancers who do not carry the variant, or unaffected carriers). No segregation data or reports of non-segregation are available in the evidence bundle. Details ▾Hide ▴

Evidence considered

No lack-of-segregation data available
exploratory search found no phenocopy or non-segregation reports.

Still missing

Segregation data in LFS families needed to assess for lack of segregation.

Sources

cspec ↗

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 applies to null variants (nonsense, frameshift, canonical +/-1,2 splice sites, initiation codon, or exon deletions). NM_000546.5:c.833C>G is a missense substitution (p.Pro278Arg) and does not fall within any PVS1 null-variant bucket per the TP53 VCEP PVS1 flowchart. Details ▾Hide ▴

Evidence considered

Missense variant p.Pro278Arg
variant_bucket=other
not a null variant eligible for PVS1.

Sources

vcep_pvs1_flowchartpvs1_variant_assessment

PM3 VCEPPM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant. TP53/Li-Fraumeni syndrome is not a recessive disorder. Details ▾Hide ▴

Evidence considered

TP53/LFS is not recessive
PM3 does not apply.

PM4 VCEPPM4 applies to in-frame deletions/insertions or stop-loss variants. This is a missense substitution, not an in-frame indel or stop-loss. Details ▾Hide ▴

Evidence considered

Missense variant
PM4 applies only to in-frame indels and stop-loss variants.

PM6 VCEPPM6 is designated Not Applicable by the TP53 VCEP v2.4.0 for use with TP53/Li-Fraumeni syndrome. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PM6 as Not Applicable.

Sources

cspec ↗

PP2 VCEPPP2 is designated Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PP2 as Not Applicable.

Sources

cspec ↗

PP5 VCEPPP5 is designated Not Applicable by the TP53 VCEP v2.4.0 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PP5 as Not Applicable for this VCEP.

Sources

cspec ↗

BP1 VCEPBP1 is designated Not Applicable by the TP53 VCEP v2.4.0, as truncating variants account for only a portion of disease-causing variants in TP53. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP1 as Not Applicable.

Sources

cspec ↗

BP2 VCEPBP2 is designated Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP2 as Not Applicable.

Sources

cspec ↗

BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a missense substitution, not an in-frame indel. Details ▾Hide ▴

Evidence considered

Missense variant
BP3 applies only to in-frame indels in repetitive regions.

BP5 VCEPBP5 is designated Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP5 as Not Applicable.

Sources

cspec ↗

BP6 VCEPBP6 is designated Not Applicable by the TP53 VCEP v2.4.0 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP6 as Not Applicable for this VCEP.

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous (silent) or intronic variants. NM_000546.5:c.833C>G is a missense variant (p.Pro278Arg) and does not qualify for BP7. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 applies only to synonymous or intronic variants.

Sources

cspec ↗

PS5 N/APS5 (same codon, different amino acid missense change previously established as pathogenic) is not defined as a separate criterion in the TP53 VCEP v2.4.0 specifications. The VCEP uses PM5 for same-residue different missense comparator analysis. PS5 is assessed under PM5 in this framework. Details ▾Hide ▴

Evidence considered

PS5 is not listed in the TP53 VCEP criteria
PM5 covers same-residue missense comparisons.

Sources

cspec ↗

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.833C>G
Protein (HGVS p.): NP_000537.3:p.(Pro278Arg)
GRCh38: chr17:7673787 G>C
GRCh37: chr17:7577105 G>C
ClinVar: 376644
COSMIC: COSV52661225

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,614,022 alleles AF 6.2e-07 · 0 homozygotes

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 v4.1

AF 6.2e-07 · 1 / 1,614,022 alleles · 0 hom

European (non-Finnish)1 / 1,180,014

8.5e-07

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-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.1957e-07; MAF= 0.00006%, 1/1614022 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.951
BayesDel: 0.608

How the predictions were used

Evidence considered

PP3-BP4-codes.xlsx: c.833C>G assigned PP3_moderate
aGVGD Class C65
BayesDel 0.607821 >= 0.16
SpliceAI max delta 0.00 < 0.2
no predicted splicing alteration.

Sources

vcep_pp3_bp4_codesspliceai ↗bayesdelcspec ↗

Evidence considered

PP3-BP4-codes.xlsx: PP3_moderate assigned
not BP4
BayesDel 0.607821 >> -0.008
aGVGD C65 precludes BP4.

Sources

vcep_pp3_bp4_codesbayesdelcspec ↗

BP7 N/ABP7 applies to synonymous (silent) or intronic variants. NM_000546.5:c.833C>G is a missense variant (p.Pro278Arg) and does not qualify for BP7. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 applies only to synonymous or intronic variants.

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.951. BayesDel score = 0.607821.

10 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

Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailand.

Galy O et al. · 2011

No paper-specific finding is recorded.

PMID 21760996 ↗
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S et al. · 2003

No paper-specific finding is recorded.

PMID 12826609 ↗
Spectrum of p53 mutations in biopsies from breast cancer patients selected for preoperative chemotherapy analysed by the functional yeast assay to predict therapeutic response.

Deissler H et al. · 2004

No paper-specific finding is recorded.

PMID 15138567 ↗
Presence of dominant negative mutation of TP53 is a risk of early recurrence in oral cancer.

Hassan NM et al. · 2008

No paper-specific finding is recorded.

PMID 18555592 ↗
Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B.

Martin AG et al. · 2009

No paper-specific finding is recorded.

PMID 20195489 ↗
High-level expression of wild-type p53 in melanoma cells is frequently associated with inactivity in p53 reporter gene assays.

Houben R et al. · 2011

No paper-specific finding is recorded.

PMID 21760960 ↗
Correlation of telomere length shortening with TP53 somatic mutations, polymorphisms and allelic loss in breast tumors and esophageal cancer.

Hao XD et al. · 2013

No paper-specific finding is recorded.

PMID 23124483 ↗
National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.

No paper-specific finding is recorded.

PMID 19042984 ↗
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.

No paper-specific finding is recorded.

PMID 22964825 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

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

gnomAD v4.1 1 / 1,614,022 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 3 Uncertain significance · 1 Likely pathogenic · 1 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

Statements for reports

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

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory). (ClinVarID = 376644)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.951. BayesDel score = 0.607821.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52661225, n = 82 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.