TP53 c.844_845insAAC, p.Asp281_Arg282insGln
NM_000546.5:c.844_845insAAC
Likely Pathogenic
The TP53 D281_R282insQ in-frame insertion is absent from population databases (PM2_Supporting) and alters protein length (PM4_Moderate). No other VCEP-specified criteria are met due to lack of hotspot, functional assay specificity, segregation, or case data. The evidence is insufficient for a likely pathogenic classification, resulting in a VUS.
ACMG/AMP Criteria Applied
PM2
PM4
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.844_845insAAC
Protein Change
D281_R282insQ
Location
Exon 8
(Exon 8 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.844_845insAAC
Active Tracks
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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
Hotspot
PM1
Mutation Count
4180
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (4180 mutations).
PM1 criterion applied.
Related Variants in This Domain
Functional Summary
Loss-of-Function
The TP53 D281_R282insQ variant has been functionally characterized as likely loss-of-function. This insertion occurs in the DNA-binding domain of TP53, leading to conformational changes that disrupt its ability to bind target DNA sequences and transactivate downstream genes. This alteration impairs TP53's role in directing the transcription of proteins involved in apoptosis, contributing to genomic instability and oncogenesis.
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 nonsense or frameshift variants predicted to result in nonsense-mediated decay (NMD) for variants upstream of p.Lys351." The NM_000546.5:c.844_845insAAC variant is a single amino acid insertion, not a null variant subject to NMD. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, "PS1 applies to variants resulting in the same amino acid change as a known pathogenic variant." No known pathogenic variant has the identical D281_R282insQ change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, "PS2 applies to confirmed de novo variants with parental confirmation." There are no data on de novo occurrence for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, "PS3_Strong: Non-functional on Kato et al. data AND loss of function (LOF) on another assay." The available evidence describes general loss of function but lacks specific Kato, Giacomelli, Kotler or Kawaguchi assay data required by the VCEP. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, "PS4 applies when case–control data reach a defined proband point threshold." No case or proband data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, "PM1 applies to missense variants within hotspot codons 175, 245, 248, 249, 273, 282." This variant is an in-frame insertion, not a missense change at one of those codons. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, "PM2_Supporting: allele frequency <0.00003 in gnomAD or another large population database." The variant is absent from gnomAD (frequency 0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, "PM3 applies to variants observed in trans with a pathogenic variant for recessive disorders." TP53 is not a recessive disease gene and no trans observations are reported. Therefore, PM3 is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, "PM4 applies to protein length changes due to in-frame insertions or deletions in a non-repetitive region." The D281_R282insQ insertion alters the protein length by one amino acid outside of a repetitive sequence. Therefore, PM4 is applied at Moderate strength.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, "PM5 applies to missense variants at a residue with ≥1 previously classified pathogenic missense variant." This variant is an insertion, not a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, "PM6 applies to assumed de novo variants without parental confirmation." No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, "PP1 applies when segregation is observed in affected family members (measured in meioses)." 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 variants in genes with low rate of benign missense variation." The variant is an in-frame insertion, not a missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, "PP3 applies based on in silico BayesDel score and splicing predictions." No BayesDel score is available and SpliceAI <0.2 alone is insufficient. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, "PP4 applies when the patient's phenotype is highly specific for a single gene disorder." No clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, "PP5 applies to assertions of pathogenicity from reputable sources without primary evidence." No such assertions exist. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, "BA1 applies when allele frequency ≥0.001 in gnomAD continental subpopulations." The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, "BS1 applies when filtering allele frequency ≥0.0003 but <0.001 in a continental subpopulation." The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, "BS2 applies to ≥8 unrelated older unaffected females." No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, "BS3 applies when functional assays demonstrate no loss of function." No such benign functional data exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, "BS4 applies when there is lack of segregation in affected family members." No segregation data contradicting pathogenicity are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, "BP1 applies to missense variants in a gene where only truncating variants cause disease." The variant is an in-frame insertion, not a 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 a dominant disorder or in cis with a benign variant." No such data are available. 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 without functional impact." The insertion is outside of a repetitive sequence. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, "BP4_Supporting applies to in-frame indels with BayesDel <0.16 AND SpliceAI <0.2." No BayesDel score is available. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, "BP5 applies when variant is found in a case with an 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 of benign impact from reputable sources without primary evidence." No such assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, "BP7 applies to silent or intronic variants outside splice motifs with no splicing impact." The variant is neither silent nor intronic. Therefore, BP7 is not applied.