Gene: TP53 (HGNC:11998)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific,Strength
Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at. Please see below for some additional helpful summary details for application of PVS1 code:




Initiation codon:


PVS1 may be applied to initiation codon variants






Nonsense or frameshift variants:


PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351


PVS1_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range


PVS1_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range


PVS1_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon






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)


PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)


PVS1_Moderate applied to splicing alterations that are predicted to shorten (<10% of the protein removed) or expand a 
TP53
 C-terminal end of unknown function (E10 donor or E11 acceptor)






Deletions


Full gene deletions: PVS1


Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1


Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1


Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1


Single- to multi-exon deletion that disrupts the reading frame and is 
NOT
 predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1


Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1


If the role of the region in protein function is unknown, if the variant removed < 10% of the protein (deletion of exon 11): PVS1_Moderate






Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1






Duplications (≥1 exon in size and must be completely contained within the 
TP53
 gene)


Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1


Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1_Strong








For variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.


Caveats
: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.


For the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:


TAD1
: aa 17-25


TAD2
: aa 48-56


Proline residues
: aa 64-92


DNA binding domain
: aa 100-292


Hinge domain
: aa 293-324


Oligomerization domain
: aa 325-356


C-terminal domain (Basic domain)
: aa 368-387


A disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for 
TP53
 PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.