TP53 c.834_835delinsA, p.Arg280GlufsTer65
NM_000546.5:c.834_835delinsA
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 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_000546.5:c.834_835delinsA
Protein Change
R280Efs*65
Location
Exon 8
(Exon 8 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 280: R280T
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 not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
4180
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (4180 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 280: R280T
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The TP53 R280Efs*65 variant is a truncating mutation in the TP53 gene, a critical tumor suppressor involved in the DNA damage response pathway. Functional studies indicate that truncating mutations in TP53 lead to the production of C-terminally truncated proteins, which are predicted to be inactivating. These truncated proteins have been experimentally shown to promote cancer cell proliferation, survival, and metastasis, partly due to their aberrant localization to the mitochondria and regulation of survival-related genes. Therefore, the TP53 R280Efs*65 variant is functionally characterized as likely oncogenic.
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 is: "Nonsense or frameshift variants predicted to result in NMD for frameshift induced PTC upstream of p.Lys351". The evidence for this variant shows: the R280Efs*65 frameshift introduces a premature stop codon at amino acid ~345, upstream of p.Lys351, and is predicted to undergo NMD. Therefore, this criterion is applied at Very Strong strength because the frameshift is upstream of p.Lys351 and leads to NMD in TP53, a known LOF mechanism.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS1 applies when a variant has the same amino acid change as a known pathogenic variant. The evidence for this variant shows: it is a frameshift, not a missense change at an amino acid position previously implicated. Therefore, this criterion is not applied because the amino acid change is novel and not identical to any known pathogenic missense change.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, PS2 (de novo occurrence) requires documented de novo events with parental confirmation. The evidence for this variant shows: no de novo segregation data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines, PS3 should not be applied if PVS1 is applied at full strength. The evidence for this variant shows: PVS1 Very Strong has been applied. Therefore, PS3 is not applied to avoid double counting LOF evidence.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, PS4 requires statistical enrichment or case-control data/point system. The evidence for this variant shows: no case or proband points data are available. Therefore, this criterion is not applied due to absence of case-control or proband point evidence.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, PM1 applies to missense variants in specific hotspot codons. The evidence for this variant shows: it is a frameshift variant, not a missense change in a hotspot. Therefore, this criterion is not applied because PM1 is only for missense variants in TP53 hotspots.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, PM2_Supporting applies when allele frequency is <0.00003 in gnomAD. The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is not observed in large population cohorts.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 applies to variants in trans with a pathogenic variant for recessive disorders. The evidence for this variant shows: TP53-related disease is dominant and no trans data apply. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 applies to in-frame indels that alter protein length without causing NMD. The evidence for this variant shows: it is a frameshift predicted to undergo NMD. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, PM5 applies to missense variants at residues with other pathogenic missense changes. The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo variants without confirmation. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, PP1 applies to segregation in affected family members. The evidence for this variant shows: no segregation data are available. 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 low rate of benign missense variation. The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, PP3 should not be used in combination with PVS1. The evidence for this variant shows: PVS1 Very Strong is applied. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to VCEP guidelines, PP4 applies to phenotypic specificity consistent with gene. The evidence for this variant shows: no specific phenotype or VAF data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 applies to reputable source assertions. The evidence for this variant shows: no external assertions. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, BA1 applies to variant allele frequency ≥0.001. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, BS1 applies to filtering allele frequency ≥0.0003 but <0.001. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, BS2 applies to observation of ≥8 unaffected older females. The evidence for this variant shows: no healthy aged individuals reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, BS3 applies to well-established functional studies showing no LOF. The evidence for this variant shows: functional studies indicate LOF. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where truncating variants are known mechanism. The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 applies to observed in trans with a pathogenic variant. The evidence for this variant shows: no trans observation. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, BP4 applies when BayesDel ≤-0.008 and SpliceAI <0.2. The evidence for this variant shows: SpliceAI predicts high impact and variant is frameshift. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 applies when variant found in a case with alternative molecular cause. The evidence for this variant shows: no alternative cause data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP6 applies to reputable source benign assertions. The evidence for this variant shows: no such assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.