TP53 c.920-1dup, p.Splice_Site
NM_000546.6:c.920-1dup
COSMIC ID: COSM6950591
Variant of Uncertain Significance (VUS)
This TP53 intronic duplication at the canonical splice acceptor position c.920-1dupG lacks any predicted splice impact, functional, segregation, or case data. Only PM2_Supporting is met (absent from population databases). Insufficient evidence of pathogenicity or benign impact leads to a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.920-1dup
Protein Change
Splice
Location
Exon 8
(Exon 8 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM6950591
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.920-1dup
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
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: "Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)". The evidence for this variant shows a SpliceAI maximum score of 0.05, below any threshold for predicted splice disruption. Therefore, this criterion is not applied because no splice alteration is predicted.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows it is an intronic duplication at c.920-1, not causing an amino acid change identical to any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". No de novo or parental testing data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: PS3 requires well-established functional studies demonstrating a damaging effect on protein function. No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "PS4: ≥8 points from proband observations (very strong) ...". No case-level or proband data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: "PM1: Missense variants within TP53 hotspot codons (e.g., 175, 245, 248, 249, 273, 282)". This variant is an intronic duplication at a splice site, not a missense in a hotspot. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "PM2: Supporting level for allele frequency <0.00003 in gnomAD or another large database". The evidence for this variant shows absence from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM3: For recessive disorders, detected in trans with a pathogenic variant". TP53 is autosomal dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM4: Protein length changes due to in-frame indels or stop-loss variants". This variant is intronic and does not change protein length directly. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "PM5: Missense variant at a residue where other pathogenic missense variants occur". This is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM6: Assumed de novo, without confirmation of paternity/maternity". No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "PP1: Cosegregation observed in family members". No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP2: Missense variant in a gene with low benign missense variation". This is an intronic duplication, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "PP3: Intronic splice variants (excluding ±1,2 positions) with SpliceAI ≥0.2". This variant is at the −1 position and SpliceAI = 0.05. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic". The variant is not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "BA1: Stand-alone benign for FAF ≥0.001 in gnomAD subpopulations". The variant is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "BS1: Filtering allele frequency ≥0.0003 but <0.001 in gnomAD". The variant is absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "BS2: Observation in ≥8 healthy females ≥60 years old". No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "BS3: Well-established functional studies show no loss of function". No functional assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "BS4: Lack of segregation in affected family members". No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP1: Missense variant in a gene for which only truncating variants cause disease". TP53 disease mechanism includes missense dominant-negative effects. Also, this is not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP2: Observed in trans with a pathogenic variant for a dominant disorder". No trans observations reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP3: In-frame deletions/insertions in repetitive regions without a known function". This variant is a single nucleotide intronic duplication not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "BP4: Silent or intronic variants outside ±1,2 positions with SpliceAI ≤0.1". This variant is at −1 position. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "BP7: Synonymous or intronic ≥+7/−21 positions with no predicted splicing impact". This variant is at the canonical −1 splice position. Therefore, this criterion is not applied.