TP53 c.421T>A, p.Cys141Ser
NM_000546.6:c.421T>A
COSMIC ID: COSM44564
Likely Pathogenic
The TP53 c.421T>A (p.Cys141Ser) variant shows moderate functional evidence of loss of function (PS3_Moderate) and is absent from population databases (PM2_Supporting). No other supporting evidence per TP53 VCEP criteria is available, yielding an overall classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PS3
PM2
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_000546.6:c.421T>A
Protein Change
C141S
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 141 in gene TP53
Alternate Identifiers
COSM44564
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.421T>A
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
329
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (329 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 141 in gene TP53
Functional Summary
The TP53 C141S variant has been functionally characterized and is associated with a likely loss of function. It is located in the DNA-binding domain of the TP53 protein. In vivo studies in yeast have shown partial loss of transactivational activity compared to the wild-type. In vitro assays indicate that while the DNA-binding affinity is similar to the wild-type, there is increased oxidative dissociation and decreased induction of p21 in cultured cells, suggesting a loss of TP53 protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.79
0.79
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 3.17primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 rule is: 'PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice) predicted to undergo NMD or critical domain disruption.' The evidence for this variant shows it is a missense change c.421T>A (p.Cys141Ser), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule is: 'Strong: Same amino acid change as a previously established Pathogenic TP53 variant.' The evidence for this variant shows no identical amino acid change previously classified as Pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the PS2 rule is: 'Very Strong: ≥8 de novo points; Strong: 4–7 points; Moderate: 2–3 points; Supporting: 1 point based on de novo evidence.' The evidence for this variant shows no de novo or parental testing data. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the PS3_Moderate rule is: 'Partially functional on Kato et al. data AND loss of function on another assay (e.g., Kotler or second assay showing low function).' The evidence for this variant shows partial transactivational activity in yeast (in vivo) and decreased p21 induction in cultured cells (in vitro) indicating loss of TP53 function. Therefore, this criterion is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the PS4 rule is: 'Very Strong: ≥8 proband points; Strong: 4–7.5 points; Moderate: 2–3.5 points; Supporting: 1–1.5 points based on case observations.' The evidence for this variant shows no case or proband data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the PM1 rule is: 'Moderate: Missense variants at codons 175, 245, 248, 249, 273, or 282; Supporting: variants with 2–9 somatic occurrences in cancerhotspots.org.' The evidence for this variant shows it is at codon 141 with zero somatic occurrences in COSMIC. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2_Supporting rule is: 'Variant allele frequency <0.00003 in gnomAD or large population databases.' The evidence for this variant shows it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM3 rule is: 'Detected in trans with a pathogenic variant in recessive disorders.' The evidence for this variant shows no trans observations or recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM4 rule is: 'Protein length changes due to in-frame indels or stop-loss.' The evidence for this variant shows no protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the PM5 rule is: 'Moderate: Missense at an amino acid where ≥1 different pathogenic missense variant has been seen; Supporting: where ≥1 likely pathogenic variant with clinical data has been seen.' The evidence for this variant shows no other pathogenic or likely pathogenic missense at Cys141. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM6 rule is: 'Assumed de novo without confirmation of paternity/maternity.' The evidence for this variant shows no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the PP1 rule is: 'Supporting: Cosegregation in 3–4 meioses; Moderate: 5–6 meioses; Strong: ≥7 meioses.' The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule is: 'Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease.' The evidence for this variant does not include gene-specific missense constraint metrics. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the PP3 rule requires aGVGD and BayesDel metrics (e.g., aGVGD C65 and BayesDel ≥0.16 for Moderate; C25–C55 and BayesDel ≥0.16 for Supporting). The evidence for this variant uses REVEL and PolyPhen-2 but lacks the required VCEP-specified scores. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the PP4 rule is: 'Supporting: Observation in tumor samples with VAF 5–35%.' The evidence for this variant shows no tumor VAF data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP5 rule is: 'Reputable source reports variant as pathogenic.' The evidence for this variant shows no such reports. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the BA1 rule is: 'Stand Alone: Filtering allele frequency ≥0.001 in gnomAD.' The evidence for this variant shows absence from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the BS1 rule is: 'Strong: Filtering allele frequency ≥0.0003 but <0.001 in gnomAD.' The evidence for this variant shows absence from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the BS2 rule is: 'Strong: ≥8 unaffected females ≥60 years; Moderate: 4–7; Supporting: 2–3.' The evidence for this variant shows no such unaffected individual data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the BS3 rule is: 'Strong: Functional on Kato et al. data AND no loss of function on another assay.' The evidence for this variant indicates loss of function in assays. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the BS4 rule is: 'Strong: Lack of segregation in affected family members.' The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP1 rule is: 'Missense variant in a gene where only truncating variants cause disease.' TP53 disease mechanism includes missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP2 rule is: 'Observed in trans with a pathogenic variant in a dominant disorder.' The evidence for this variant shows no such observation. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP3 rule is: 'In-frame indels in repetitive regions without known function.' The evidence for this variant shows a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the BP4 rule is: 'Supporting: BayesDel <0.16 and >-0.008 with no splicing impact.' The evidence for this variant lacks BayesDel data. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP5 rule is: 'Variant found in a case with an alternate molecular basis for disease.' No such alternate basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP6 rule is: 'Reputable source reports variant as benign.' The evidence for this variant shows no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the BP7 rule is: 'Supporting: Synonymous or intronic variant outside core splice sites with no predicted splicing impact.' The evidence for this variant shows a missense change. Therefore, this criterion is not applied.