Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.6 | MANE Select | 2512 nt | 143–1324 |
| NM_000546.4 | Alternative | 2586 nt | 198–1379 |
| NM_000546.2 | Alternative | 2629 nt | 252–1433 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change falls in intron 3 of the TP53 gene. It does not directly change the encoded amino acid sequence of the TP53 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Li-Fraumeni syndrome (PMID: 11420676, 24382691, 28681140). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS3-11 C>G. ClinVar contains an entry for this variant (Variation ID: 638852). RNA analysis provides insufficient evidence to determine the effect of this variant on TP53 splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TP53 97-11c>G variant has not been functionally characterized, and its biological significance remains unknown.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.59 | -11 bp |
| Donor Loss (DL) | 0.01 | -289 bp |
| Acceptor Gain (AG) | 0.97 | -1 bp |
| Donor Gain (DG) | 0.0 | -89 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies only to canonical splice variants (±1,2 intronic positions) or validated null mechanisms. The variant c.97-11C>G is outside the ±1,2 positions and lacks experimental RNA evidence. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. c.97-11C>G is intronic with no amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 requires confirmed de novo occurrence with parental testing. No de novo data are available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires well-validated functional assay evidence of loss of function. No functional studies are available for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires proband case points for LFS-associated cancers. No case-level data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to missense variants in TP53 hotspot codons. c.97-11C>G is intronic. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 Supporting: "Variant should have an allele frequency of less than 0.00003 in gnomAD...". The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG/AMP guidelines, PM3 applies to recessive gene inheritance with trans observations. TP53 is autosomal dominant and no trans data exist. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG/AMP guidelines, PM4 applies to protein length changes from in-frame indels. c.97-11C>G does not alter protein length directly. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 applies to missense variants at residues with other pathogenic missense changes. c.97-11C>G is intronic. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG/AMP guidelines, PM6 applies to assumed de novo occurrence without confirmation. No de novo data exist. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires cosegregation in multiple meioses. No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG/AMP guidelines, PP2 applies to missense variants in genes with low benign missense variation. This is intronic, not missense. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines, Intronic splice variants (excluding ±1,2) with SpliceAI ≥0.2 qualify for PP3 Supporting: "SpliceAI ≥ 0.2". The variant has a SpliceAI score of 0.97. Therefore, PP3 is applied at Supporting strength.
PP4 (Not Applied)
According to VCEP guidelines, PP4 requires phenotype specificity for TP53-related disorders. No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to VCEP guidelines, PP5 is not recommended for TP53 variant interpretation. Although ClinVar entries report pathogenicity, VCEP excludes PP5. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 Stand Alone applies for a filtering allele frequency ≥0.1%. The variant is absent. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 Strong applies for filtering allele frequency ≥0.0003. The variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 requires observation in healthy older individuals. No such data exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional assay evidence of no loss of function. No functional data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No family data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG/AMP guidelines, BP1 applies to missense variants in genes where truncating variants cause disease. c.97-11C>G is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG/AMP guidelines, BP2 applies to trans occurrences with a pathogenic variant. Not applicable. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG/AMP guidelines, BP3 applies to in-frame repeats. Not applicable. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 applies when SpliceAI <0.2 for intronic variants. Here SpliceAI=0.97 predicts impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG/AMP guidelines, BP5 applies if variant found in gene for an unrelated phenotype. Not applicable. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG/AMP guidelines, BP6 applies to non-public reputable source reports of benign. VCEP does not use BP6. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 Supporting applies to intronic variants at ≥+7/≤−21 with SpliceAI ≤0.1. c.97-11C>G has SpliceAI=0.97. Therefore, BP7 is not applied.