TP53 c.824_826delinsTT, p.Cys275PhefsTer70
NM_000546.6:c.824_826delinsTT
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_000546.6:c.824_826delinsTT
Protein Change
C275Ffs*70
Location
Exon 8
(Exon 8 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 275 in gene TP53
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
No evidence of other pathogenic variants at position 275 in gene TP53
Functional Studies
Summary
The TP53 C275Ffs*70 variant is a truncating mutation in the tumor suppressor gene TP53. Functional evidence indicates that truncating mutations in TP53 lead to the production of C-terminally truncated proteins, which are predicted to be inactivating. Experimental studies have shown that these mutations promote cancer cell proliferation, survival, and metastasis, partly due to aberrant protein localization affecting cell survival pathways. Therefore, the TP53 C275Ffs*70 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, PVS1 applies to frameshift variants predicted to undergo NMD when the PTC is upstream of p.Lys351. The variant c.824_826delGTGinsTT causes a frameshift at codon 275 with a premature stop 70 amino acids downstream, which is upstream of p.Lys351 and predicted to trigger NMD. Therefore, PVS1 is applied at Very Strong strength.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, PS1 applies to variants that result in the same amino acid change as a known pathogenic variant. The c.824_826delGTGinsTT variant is a frameshift (C275Ffs*70), not a missense change at the same residue as a known pathogenic variant. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS2 applies to confirmed de novo occurrences. No parental testing or de novo data are provided for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP caveats, PS3 should not be applied at any strength if PVS1 is applied at full strength. PVS1 has been applied at Very Strong strength. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS4 requires statistical evidence of increased prevalence in affected individuals. No case–control or proband count data meeting PS4 thresholds are provided. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, PM1 applies to missense variants at specific hotspot codons or cancer hotspots. The c.824_826delGTGinsTT variant is a frameshift, not a missense change. Therefore, PM1 is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, PM2_Supporting applies when allele frequency is <0.00003 in gnomAD. This variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 applies to variants in trans with a pathogenic variant in recessive disorders. TP53-related disease is dominantly inherited and no trans observation data are provided. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes in non-truncating variants or in-frame indels. The variant is a truncating frameshift covered by PVS1. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at a residue with other pathogenic missense variants. The variant is a frameshift and does not meet PM5 criteria. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation. No parental data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, PP1 requires segregation in multiple affected family members. No segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. The variant is a frameshift, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, PP3 applies to missense or splice variants with in silico support. This is a truncating variant and in silico splicing predictions show minimal impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to VCEP guidelines, PP4 requires a specific phenotype with high specificity. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 applies to variants reported as pathogenic by reputable sources without primary data. No such reports are available. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, BA1 applies for allele frequency ≥0.001. This variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, BS1 applies for allele frequency ≥0.0003 but <0.001. The variant is not observed in population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, BS2 applies when ≥8 unaffected older females are observed. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, BS3 applies when functional assays demonstrate no loss of function. This variant is functionally inactivating and PVS1 is applied. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected members. No segregation data are available. Therefore, BS4 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 the known mechanism. The variant is truncating and PVS1 is applied. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in cis with a pathogenic variant or in trans for dominant disorder. No such data are present. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a frameshift indel, not an in-frame change. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, BP4 applies to missense or splice variants with benign computational evidence. This frameshift variant lacks significant splicing predictions and is inactivating; thus BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No alternate cause is reported. Therefore, BP5 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 primary data. No such reports are available. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This is a coding frameshift. Therefore, BP7 is not applied.