TP53 c.993+284C>T, p.?
NM_000546.5:c.993+284C>T
Variant of Uncertain Significance (VUS)
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
BP4
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_000546.5:c.993+284C>T
Protein Change
?
Location
Exon 9
(Exon 9 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.993+284C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00185%
Rare
Highest in Population
African/African American
0.00502%
Rare
Global: 0.00185%
African/African American: 0.00502%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 215690Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00185%, 4/215690 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00502%, 1/19910 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Uncertain significance (2 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
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 for PVS1: 'PVS1 applies to canonical splice variants (±1,2 positions) or null variants leading to NMD in TP53.' The variant is located at +284 intronic position, outside the canonical splice site. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: 'Applies to variants with same amino acid change as established pathogenic variant.' This variant is non-coding and does not result in an amino acid change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PS2: 'Requires confirmed de novo occurrence with parental testing.' No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3: 'Requires non-functional or loss-of-function evidence from validated TP53 assays.' No functional studies have been performed. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4: 'Requires case-control or proband point totals for LFS cancers.' No such case data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1: 'Applies to hotspot missense codons in DNA-binding domain.' This variant is intronic and not a missense change at a hotspot codon. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines for PM2_Supporting: 'Variant allele frequency must be <0.00003 overall and <0.00004 in any ancestry group.' Although the overall MAF is 0.0000185 (<0.00003), the African/African-American subpopulation frequency is 0.0000502 (>0.00004). Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM3: 'Applies to variants observed in trans with a pathogenic variant in a recessive disorder.' TP53-related conditions are dominant and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM4: 'Applies to protein length changes such as in-frame indels.' This variant is intronic with no protein length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: 'Applies to missense changes at residues with other pathogenic missense variants.' This variant is intronic. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines for PM6: 'Applies to assumed de novo without confirmation.' No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1: 'Requires segregation data in multiple meioses.' No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2: 'Applies to missense variants in genes with low rate of benign missense.' This variant is intronic. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP3: 'Requires multiple lines of computational evidence supporting a deleterious effect.' SpliceAI score is 0.16 (below typical splicing impact threshold) and no other in silico tool predicts deleteriousness. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for PP4: 'Requires specific TP53-related phenotype observations.' No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP5: 'Applies to assertions from reputable sources without supporting evidence.' ClinVar submissions are conflicting (Likely benign and VUS). Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: 'Requires filtering allele frequency ≥0.001 in any gnomAD ancestry group.' The highest subpopulation MAF is 0.0000502, below the BA1 threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: 'Requires FAF ≥0.0003 but <0.001 in a gnomAD ancestry group.' The highest subpopulation MAF is 0.0000502, below 0.0003. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2: 'Requires ≥2 unrelated older unaffected individuals.' No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: 'Requires functional assays demonstrating no loss of function in TP53.' No functional assay data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BS4: 'Requires lack of segregation in affected family members.' No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP1: 'Applies to missense variant in a gene where only truncating variants cause disease.' This variant is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP2: 'Applies to observed in trans with pathogenic for dominant disorder.' Not applicable for this TP53 variant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3: 'Applies to in-frame indels in repetitive regions.' This variant is intronic, not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines for BP4: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' SpliceAI predicts no splicing impact (max score 0.16) and other tools show no deleterious effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP5: 'Applies when variant found in cis with a pathogenic variant.' No cis observations exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP6: 'Applies to assertions from reputable sources without evidence.' ClinVar submissions are conflicting. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7: 'Applies to intronic variants outside ±1,2 with SpliceAI ≤0.1.' SpliceAI = 0.16, above the BP7 cutoff. Therefore, BP7 is not applied.