TP53 c.874A>T, p.Lys292Ter
NM_000546.6:c.874A>T
COSM44894
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Pathogenic
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
8 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.874A>T
Protein Change
K292*
Location
Exon 8
(Exon 8 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM44894
Variant interpretation based on transcript NM_000546.6
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000000% MAF).
Classification
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Studies
Summary
The TP53 K292* variant is a truncating mutation in the tumor suppressor gene TP53. Functional studies indicate that truncating mutations in TP53 lead to the production of C-terminally truncated protein forms, which are predicted to be inactivating. These mutations have been experimentally shown to promote cancer cell proliferation, survival, and metastasis, partly due to aberrant localization of truncated proteins to the mitochondria, affecting genes involved in cell survival. Therefore, the TP53 K292* variant is functionally characterized as damaging.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 states: 'Nonsense or frameshift variants: PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351.' The evidence for this variant shows a truncating change (K292*) which is upstream of p.Lys351. Therefore, this criterion is applied at Very Strong strength because the variant is predicted to result in loss of function.
PS3
PS3 (Strong)
According to VCEP guidelines (and consistent with the provided functional study evidence), the rule for PS3 is: 'Strong Strength: Strong Non-functional on Kato et al. data AND loss of function (LOF) on another assay.' The evidence for this variant shows that functional studies indicate that truncating mutations in TP53 produce C-terminally truncated proteins that are damaging, promoting cancer cell proliferation and survival. Therefore, this criterion is applied at Strong strength.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for PM2, the rule/finding is: 'This rule should be applied at supporting level if the variant has an allele frequency less than designated thresholds in population databases.' The evidence for this variant shows it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows that it has been reported in ClinVar as Pathogenic by a reputable clinical laboratory. Therefore, this criterion is applied at Supporting strength.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant' which applies to missense changes. The evidence for this variant, being a truncating (nonsense) variant, does not meet the criteria. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS2 is used for confirmed de novo occurrences with parental testing. The evidence for this variant does not include documented de novo status. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS4 requires case-control data showing increased prevalence in affected individuals. The evidence for this variant does not include such data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, PM1 applies to missense variants located in mutational hotspots (e.g., codons 175, 245, etc.). The evidence for this variant is a nonsense variant, not a missense change. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders when a variant is observed in trans with a pathogenic variant. The evidence for this variant does not involve recessive inheritance or compound heterozygosity. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 applies to in-frame deletions/insertions or protein length changes other than those causing nonsense-mediated decay. The evidence for this variant is a truncating (nonsense) change and not an in-frame alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, PM5 applies to missense variants at an amino acid residue where other pathogenic missense changes have been observed. The evidence for this variant is a nonsense variant and does not pertain to missense alterations. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 is used for assumed de novo variants where parental testing is not available. The evidence for this variant does not include de novo occurrence data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, PP1 is used if there is documented segregation in families. The evidence for this variant does not include segregation data across multiple meioses. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with a low rate of benign missense variation. The evidence for this variant, being a truncating mutation, is not applicable. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, PP3 applies to computational evidence supporting a deleterious effect, typically used for missense or splicing variants. The evidence for this variant does not include supportive computational predictions (and BP4 information was noted instead for splicing prediction), so PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP4 is used when a patient’s phenotype is highly specific for a disease with a single genetic etiology. The evidence for this variant does not include detailed phenotype or segregation data to warrant PP4. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, BA1 is applied if the allele frequency is above a specific benign threshold. The evidence for this variant shows it is absent from population databases, which does not meet the benign frequency threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, BS1 applies when the allele frequency is higher than expected for the disorder. As the evidence shows absence in the population, BS1 is not applicable. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, BS2 applies when multiple unaffected individuals over a certain age are identified carrying the variant. The evidence does not provide such information. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, BS3 is intended for variants with functional studies showing normal function. The evidence for this variant shows damaging functional effects. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS4 is applied when there is a lack of segregation in affected family members. The evidence for this variant does not include segregation analysis data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to VCEP guidelines, BP1 is used for missense variants in genes where loss-of-function is the known mechanism of disease. Since the variant is a truncating variant and loss-of-function is the mechanism, BP1 is not applicable. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 is used when the variant is observed in trans with a pathogenic variant for a dominant condition or in cis with a benign variant. The evidence for this variant does not include such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame deletions/insertions that do not disrupt function. The evidence for this variant is a nonsense mutation, so BP3 is not applicable. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, BP4 relates to computational predictions indicating a benign effect. The evidence for this variant, a truncating variant, does not warrant computational evidence assessment (and PP3/BP4 should not be applied with PVS1). Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 is used when a variant is found in a case with an alternate molecular basis for disease. The evidence for this variant does not provide such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP6 applies to variants reported as benign by reputable sources without available supporting evidence. The evidence for this variant is reported as pathogenic in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, BP7 is intended for synonymous or intronic variants with no predicted splicing impact. The evidence for this variant is a nonsense variant, so BP7 is not applicable. Therefore, this criterion is not applied.