TP53 c.97-11C>G, p.?
NM_000546.6:c.97-11C>G
COSMIC ID: COSN1201754, COSN5842796
Variant of Uncertain Significance (VUS)
The TP53 c.97-11C>G variant is absent from population databases (PM2 Supporting) and predicted to impact splicing by SpliceAI (PP3 Supporting). No additional evidence supports or refutes pathogenicity. Per VCEP TP53 guidelines, it remains a Variant of Uncertain Significance.
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.97-11C>G
Protein Change
?
Location
Exon 3
(Exon 3 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN1201754, COSN5842796
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.97-11C>G
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
1 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
2 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This 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.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
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 97-11c>G 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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.82
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires cosegregation in multiple meioses. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
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
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
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires phenotype specificity for TP53-related disorders. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 Strong applies for filtering allele frequency ≥0.0003. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires observation in healthy older individuals. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No family data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
According to standard ACMG/AMP guidelines, BP2 applies to trans occurrences with a pathogenic variant. Not applicable. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG/AMP guidelines, BP3 applies to in-frame repeats. Not applicable. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.