Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| 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 variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25584008]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23259501, 25584008, 1565143, 20586629].
This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 241 of the TP53 protein (p.Ser241Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 23259501, 25584008, 28279309, 32817165). ClinVar contains an entry for this variant (Variation ID: 376663). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 25584008, 30224644). This variant disrupts the p.Ser241 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 23031740, 26911350, 28975465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Pathogenic (4 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TP53 S241Y variant, located in the DNA-binding domain of the TP53 protein, has been functionally characterized and shown to have a damaging effect. Experimental evidence indicates that this variant results in a loss of transactivation activity of p53 target genes and a decreased ability to suppress colony formation in cell culture assays.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -401 bp |
| Donor Loss (DL) | 0.0 | 322 bp |
| Acceptor Gain (AG) | 0.01 | 2 bp |
| Donor Gain (DG) | 0.0 | 50 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines: 'PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense and frameshift variants upstream of p.Lys351.' This variant is a missense change (S241Y) and not predicted to undergo NMD. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines: 'PS1 applies to variants that result in the same amino acid change as a previously established pathogenic variant.' There is no known pathogenic variant at codon 241 producing the same amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines: 'PS2 requires confirmed de novo occurrence with adequate parental testing points.' There are no de novo data for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines: 'PS3_Strong requires non-functional on Kato et al. data AND loss of function on another assay.' The available functional data do not specify results from Kato or Giacomelli assays. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines: 'PS4 requires a proband point total ≥2 for Moderate or ≥4 for Strong based on case data.' No case or segregation data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines: 'PM1 applies to missense variants within codons 175, 245, 248, 249, 273, or 282.' This variant affects codon 241. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines: 'PM2_Supporting: allele frequency <0.00003 in gnomAD.' This variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines: 'PM3 applies to variants observed in trans with a pathogenic variant for a recessive disorder.' TP53 disease is autosomal dominant and no trans observations are reported. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: 'PM4 applies to protein length–altering variants such as in-frame insertions/deletions.' This is a missense variant. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines: 'PM5_Strong applies to a missense variant at a residue with ≥2 previously established pathogenic missense variants.' No other pathogenic variants are reported at residue 241. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines: 'PM6 applies to assumed de novo occurrences without confirmation.' No de novo information is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines: 'PP1 requires cosegregation in affected family members (Supporting: 3–4 meioses, Moderate: 5–6, Strong: ≥7).' No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: 'PP2 applies to missense variants in genes with low rates of benign missense variation.' TP53 has known benign and pathogenic missense variants and does not meet this criterion. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines: 'PP3_Moderate requires BayesDel ≥0.16 and aGVGD C65; PP3_Supporting has lower thresholds.' Computational data are mixed and BayesDel scores are not provided. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines: 'PP4 applies when the patient’s phenotype is highly specific to a single gene disorder.' No phenotype or clinical context is provided. Therefore, PP4 is not applied.
PP5 (Supporting)
According to standard ACMG guidelines: 'PP5: a reputable source reports the variant as pathogenic.' ClinVar submissions include Likely Pathogenic and Pathogenic assertions. Therefore, PP5 is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines: 'BA1 applies to variants with filtering allele frequency ≥0.001 in gnomAD.' This variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines: 'BS1 applies to filtering allele frequency ≥0.0003 but <0.001 in gnomAD.' This variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines: 'BS2 requires ≥8 unrelated older unaffected females.' No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines: 'BS3_Strong requires functional normal on Kato and no loss of function on another assay.' Functional data show damaging effects. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines: 'BS4 applies to lack of segregation in affected family members.' No segregation evidence is provided. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: 'BP1 applies to missense variants in genes where only truncating variants cause disease.' TP53 has known pathogenic missense variants. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines: 'BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder.' No such observations exist. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: 'BP3 applies to in-frame indels in repetitive regions.' This is a missense change. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines: 'BP4_Moderate requires BayesDel ≤–0.008 and SpliceAI <0.2.' BayesDel is unavailable and in silico predictions are mixed. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines: 'BP5 applies when a variant in a gene has an alternate genetic cause for disease.' No alternate cause is indicated. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines: 'BP6 applies when a reputable source reports a variant as benign.' No benign assertions are reported. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines: 'BP7 applies to synonymous or intronic variants with no splicing impact.' This is a missense variant. Therefore, BP7 is not applied.