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. Expression of this variant in TP53-null cells results in decreased transactivation of p53 target genes and fails to suppress colony growth, indicating a loss of normal TP53 tumor suppressor function.
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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, the rule for PVS1 applies only to null variants (nonsense, frameshift, canonical splice, initiation codon, or whole‐gene deletions). The evidence for this variant shows it is a missense change (S241Y). Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 applies when a variant results in the same amino acid change as a known pathogenic variant using the same nucleotide change context. The evidence for this variant shows no previously established pathogenic variant with the same amino acid change at S241. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 applies to confirmed de novo occurrences with appropriate parental testing. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well‐established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: TP53 S241Y expressed in TP53‐null cells exhibits decreased transactivation of p53 target genes and fails to suppress colony growth, indicating loss of normal TP53 tumor suppressor function. Therefore, this criterion is applied at Strong strength because well‐established functional studies support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, PS4 applies based on case counts meeting defined proband‐point thresholds. No case or pedigree data meeting the PS4 threshold are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to missense variants at specified hotspot codons (175, 245, 248, 249, 273, 282) or germline variants with ≥10 somatic observations at the same amino acid. This variant is at codon 241, not in a specified hotspot, and lacks somatic hotspot evidence. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2_Supporting is: 'Variant should have an allele frequency of less than 0.00003 in gnomAD or another large database.' The evidence for this variant shows it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to detection of a variant in trans with a pathogenic variant in recessive disorders. TP53 is not associated with recessive inheritance in this context and no in trans data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes due to in‐frame indels or stop‐loss variants. This is a missense variant without protein length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 applies to a missense change at a residue where ≥1 other different pathogenic missense variant has been observed. No other TP53 pathogenic missense variants at residue 241 are documented. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 applies to assumed de novo cases without full confirmation. No de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies based on cosegregation data meeting defined meiosis thresholds. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies when a gene has a low rate of benign missense variants and missense variants are a common mechanism of disease. TP53 does not meet these gene‐specific criteria for PP2, and the VCEP does not apply PP2 for TP53. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies at Moderate strength for missense variants meeting a BayesDel ≥0.16 and no predicted splice impact. BayesDel score is not available and computational evidence is mixed. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies when the patient’s phenotype matches a specific TP53‐associated syndrome and additional VAF criteria are met. No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to ACMG practice and VCEP clarification, PP5 (reputable source assertion without available evidence) is no longer considered valid. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies when allele frequency is ≥0.001 in gnomAD. This variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies when allele frequency is between 0.0003 and 0.001. This variant is absent from gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies when ≥8 unrelated older female controls without cancer carry the variant. No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies when functional assays demonstrate no loss of function. Functional studies show loss of function for this variant. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies when there is lack of segregation in affected family members. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies when missense variants in a gene where only truncating variants cause disease. TP53 disease mechanism includes missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when a variant is observed in cis/trans with a pathogenic variant in a manner inconsistent with pathogenicity. No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in‐frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).' The evidence for this variant shows mixed in silico predictions for protein impact but SpliceAI predicts no splicing impact (score 0.01). Therefore, this criterion is applied at Supporting strength because computational evidence does not predict a deleterious effect.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternative molecular basis for disease. No alternative molecular diagnosis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to ACMG practice, BP6 (reputable source assertion without evidence) is no longer considered valid. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to synonymous or intronic variants outside core splice sites with no predicted splice impact. This is a missense variant. Therefore, this criterion is not applied.