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 has been functionally characterized and demonstrates a damaging effect. It is located in the DNA-binding domain of the TP53 protein. Functional assays show 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.
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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 is: 'PVS1 applies to predicted null variants (nonsense, frameshift, canonical splice, initiation codon) expected to undergo NMD.' 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 is: 'Same amino acid change as a previously established pathogenic variant at the same codon.' The evidence for this variant shows: no known pathogenic variant resulting in Ser241Tyr via a different nucleotide change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'De novo occurrence in a patient with the disease and no family history.' The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 requires: 'Strong: non-functional on Kato et al. AND LOF on another assay; Moderate/Supporting: specific combinations of Kato, Giacomelli, Kotler, Kawaguchi data.' The evidence for this variant shows: a loss of transactivation assay but no data from Kato, Giacomelli, Kotler or Kawaguchi studies. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Requires aggregation of case points (≥4 points for Strong, etc.).' The evidence for this variant shows: no case-level or cohort data available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate: missense variants at hotspot codons 175, 245, 248, 249, 273, 282.' The evidence for this variant shows: position 241 is within the DNA-binding domain but not a defined hotspot. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population.' The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant meets the VCEP rarity threshold.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: TP53 is autosomal dominant and no recessive in trans data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes (indels, in-frame deletions/insertions).' The evidence for this variant shows: it is a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Missense variant at a residue where ≥1 different pathogenic missense variant has been seen (Moderate) or ≥2 (Strong).' The evidence for this variant shows: no other Ser241 missense variants classified as pathogenic by VCEP. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity/maternity.' The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting/Moderate/Strong based on number of segregations across families.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense and where such variants are a common mechanism.' The evidence for this variant shows: no gene-specific benign rate data provided. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Moderate/Supporting based on BayesDel and SpliceAI thresholds.' The evidence for this variant shows: BayesDel score not provided, and SpliceAI <0.2 but BayesDel data missing. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Phenotype or family history highly specific for a single gene disorder.' The evidence for this variant shows: no clinical phenotype information provided. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense in a gene where only truncating variants cause disease.' The evidence for this variant shows: TP53 disease mechanism includes missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a dominant pathogenic variant.' The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in repetitive regions without known function.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Moderate: BayesDel ≤ -0.008 AND SpliceAI < 0.2.' The evidence for this variant shows: SpliceAI <0.2 but BayesDel score not provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar lists 1 laboratory as Likely pathogenic and 4 laboratories as Pathogenic. Therefore, this criterion is applied at Supporting strength because multiple reputable sources assert pathogenicity without underlying primary data.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Filtering allele frequency ≥0.001 in gnomAD continental subpopulations.' The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Filtering allele frequency ≥0.0003 but <0.001 in a population.' The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Observation in ≥8 unaffected females ≥60 years old without cancer.' The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong: functional assay shows no LOF; Supporting: multiple assays without LOF.' The evidence for this variant shows: assays indicate LOF. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternative cause reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign but evidence is not available.' The evidence for this variant shows: no reputable benign assertions. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Synonymous or intronic outside core splice sites with SpliceAI ≤0.1.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.