TP53 c.783-6_814del, p.?
NM_000546.6:c.783-6_814del
Variant of Uncertain Significance (VUS)
NM_000546.6:c.783-6_814del in TP53 deletes non-canonical splice acceptor sequence and coding region, is absent from population databases (PM2_Supporting) and computationally predicted to disrupt splicing (PP3_Supporting). No additional evidence to support pathogenicity or benign impact is available, resulting in a VUS classification.
ACMG/AMP Criteria Applied
PM2
PP3
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.783-6_814del
Protein Change
?
Location
Exon 7-8
(Exon 7 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.783-6_814del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
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 Summary
The TP53 783-6_814del variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PVS1 applies to canonical splice variants (+/-1,2 intronic positions) resulting in PTC and NMD.' This variant spans c.783-6 to c.814 (position -6, non-canonical). Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant.' The protein change is unknown and no matching pathogenic amino acid change is reported. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PS2 applies for confirmed de novo variants with paternity and maternity confirmed.' No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS3 applies when well-established functional studies demonstrate a damaging effect.' No functional studies are available for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PS4 applies when case-control data show increased prevalence in affected individuals.' No case-control or proband count data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM1 applies to missense variants in defined TP53 mutational hotspots.' This variant is a splice/intronic deletion, not a missense change. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'PM2_Supporting: allele frequency <0.003% in gnomAD.' The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM3 applies to variants detected in trans in recessive disorders.' TP53 is a dominant gene and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM4 applies to in-frame indels that alter protein length.' This deletion is predicted to cause a frameshift, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM5 applies to missense variants at residues where other pathogenic missense changes occur.' This is a splice/intronic deletion, not a missense variant. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM6 applies to assumed de novo variants without confirmation.' No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP1 applies for segregation in families meeting LFS cancer criteria.' No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PP2 applies to missense changes in genes with low benign variation.' This is a splice/intronic deletion, not a missense variant. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: 'PP3_Supporting applies to intronic splice variants (excluding +/-1,2) with SpliceAI ≥0.2.' SpliceAI predicts acceptor loss with score 1.0. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP4 applies for phenotype specificity matching LFS criteria.' No phenotypic match data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PP5 applies to assertions by reputable sources without available evidence.' No such assertions exist. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BA1 applies for allele frequency ≥0.1% in gnomAD.' The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS1 applies for filtering allele frequency ≥0.0003.' The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS2 applies for ≥8 unaffected females ≥60 years old without cancer.' No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS3 applies when functional data show no loss of function.' No functional data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS4 applies for lack of segregation with disease.' 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 changes in LOF disease genes.' This variant is splice/intronic, not missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP2 applies when variant is observed in trans with a pathogenic variant in dominant disorder.' No trans observations exist. 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 deletion is frameshift-predicted and not in a repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP4 applies when computational tools predict no impact (SpliceAI <0.2).' SpliceAI predicts high impact (1.0). Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP5 applies if variant found with alternate molecular cause.' No such data are available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP6 applies to assertions by non-expert sources.' No such assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP7 applies to synonymous or intronic variants outside ±1,2 with SpliceAI ≤0.1.' This deletion affects the splice acceptor region and has SpliceAI 1.0. Therefore, BP7 is not applied.