17-7675087-GCG-AGA
Variant summary
Our verdict is Likely pathogenic. The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PS1_ModeratePM1PM2PM5
The NM_000546.6(TP53):c.523_525delCGCinsTCT (p.Arg175Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R175H: Pathogenic (ClinVar VariationId 12374, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R175?: Uncertain_significance (ClinVar VariationId 2687679, 0 stars); p.R175C: Uncertain_significance (ClinVar VariationId 245851, 3 stars); p.R175= (synonymous): Benign/Likely_benign (ClinVar VariationId 1527986, 2 stars) A different missense variant at the same amino acid position has been reported as oncogenic in ClinVar. The variant position is a cancer hotspot (cancerhotspots.org) with 2850 samples affected at this amino acid position. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.
Frequency
Genomes: not found (cov: 33)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 6.16
Publications
0 publications found
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
TP53 Gene-Disease associations (from GenCC):
- breast cancerInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- Li-Fraumeni syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
- Li-Fraumeni syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
- adrenocortical carcinoma, hereditaryInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- bone marrow failure syndrome 5Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- colorectal cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- choroid plexus carcinomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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new If you want to explore the variant's impact on the transcript NM_000546.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript:
Our verdict: Likely_pathogenic. The variant received 8 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PS1Same amino acid change as known pathogenic | Same AA change, 0-star ClinVar pathogenic — moderate (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 0 stars). | ||
| PM1Mutational hot spot or critical domain | Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 38 pathogenic, 5 benign (OR vs. background: 35.0). | ||
| PM2Absent/extremely low in population databases | Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate. | ||
| PM5Novel missense at known pathogenic residue | Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R175H: Pathogenic (ClinVar VariationId 12374, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.R175?: Uncertain_significance (ClinVar VariationId 2687679, 0 stars); p.R175C: Uncertain_significance (ClinVar VariationId 245851, 3 stars); p.R175= (synonymous): Benign/Likely_benign (ClinVar VariationId 1527986, 2 stars) |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
TP53 | MANE Select | c.523_525delCGCinsTCT p.Arg175Ser | missense | N/A | Prot: NP_000537.3 | |
TP53 | c.523_525delCGCinsTCT p.Arg175Ser | missense | N/A | Prot: NP_001119584.1 | ||
TP53 | c.523_525delCGCinsTCT p.Arg175Ser | missense | N/A | Prot: NP_001394191.1 |
HGVSc / HGVSpc.523_525delCGCinsTCTp.Arg175Ser
Exon rankN/A
missense
Prot: NP_000537.3
HGVSc / HGVSpc.523_525delCGCinsTCTp.Arg175Ser
Exon rankN/A
missense
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
TP53 | TSL:1MANE Select | c.523_525delCGCinsTCT p.Arg175Ser | missense | N/A | Prot: ENSP00000269305.4 UniProt: | |
TP53 | TSL:1 | c.523_525delCGCinsTCT p.Arg175Ser | missense | N/A | Prot: ENSP00000391478.2 UniProt: | |
TP53 | TSL:1 | c.406_408delCGCinsTCT p.Arg136Ser | missense | N/A | Prot: ENSP00000478219.1 UniProt: |
HGVSc / HGVSpc.523_525delCGCinsTCTp.Arg175Ser
Exon rankN/A
missense
Prot: ENSP00000269305.4UniProt: P04637-1
HGVSc / HGVSpc.523_525delCGCinsTCTp.Arg175Ser
Exon rankN/A
missense
Prot: ENSP00000391478.2UniProt: P04637-1
HGVSc / HGVSpc.406_408delCGCinsTCTp.Arg136Ser
Exon rankN/A
missense
Prot: ENSP00000478219.1UniProt: P04637-4
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
Common (AF > 0.05 / Hom > 5)
Rare (AF ≤ 0.0001 / Hom ≤ 1)
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 2 sources | |||||
GnomAD3 genomes | Cov:33 | ||||
GnomAD4 genome | Cov:33 | ||||
Showing 2 sources
ClinVar
Not reported inComputational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
PhyloP100 | Uncertain | 6.2 |
Showing 1 of 1 scores
Splicing Scores
No splicing scores have been computed for this variant.
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
MaveDB functional evidence
1 abnormal
8 normal (RUO)
6 no calibration
15 assays found for this variant.
Clinical calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).
Research-use-only (RUO) calibration: 0 functionally abnormal (PS3), 8 functionally normal (BS3).
No calibration: 6 assays (score only).
RUO results are not validated; give them no weight next to the clinical ones.
- Gene
- TP53
- Assay type
- Cell fitness
- Mechanism
- DNA damage response, signal transduction by p53 class mediator and MDM2/MDM4 family protein binding
- Model system
- Immortalized human cells (Homo sapiens)
- Score
- -0.519 · p.Arg175Ser (assay numbering)
Systematic integration of multiplexed functional data (TP53)
- Gene
- TP53
- Assay type
- Not applicable (trained predictor)
- Mechanism
- Loss of function or dominant-negative effect
- Model system
- Not applicable (Not Applicable)
- Score
- -0.0499 · p.Arg175Ser (assay numbering)
- Gene
- TP53
- Assay type
- Cell fitness
- Mechanism
- Double-strand break repair, damage response, signal transduction by p53 class mediator and Response to etoposide
- Model system
- Immortalized human cells (Homo sapiens)
- Score
- 0.174 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 p53R2 promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 137 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 Noxa promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 132 · p.Arg175Ser (assay numbering)
Classification of TP53 function
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Not applicable (Saccharomyces cerevisiae)
- Score
- 51.6 · p.Arg175Ser (assay numbering)
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 53.4 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 p53AIP1 promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 49.8 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 GADD45 promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 64.3 · p.Arg175Ser (assay numbering)
- Gene
- TP53
- Assay type
- Cell fitness
- Mechanism
- DNA damage response, signal transduction by p53 class mediator and MDM2/MDM4 family protein binding
- Model system
- Immortalized human cells (Homo sapiens)
- Score
- 0.543 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 MDM2 promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 37.7 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 BAX promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 46.2 · p.Arg175Ser (assay numbering)
Arrayed yeast-based assay of TP53 p21WAF1 promoter
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Yeast (Saccharomyces cerevisiae)
- Score
- 32.2 · p.Arg175Ser (assay numbering)
Nutlin-3a treatment of TP53 variant-expressing K562 reporter cells
- Gene
- TP53
- Assay type
- Reporter
- Mechanism
- Core promoter sequence-specific DNA binding
- Model system
- Immortalized human cells (Homo sapiens)
- Score
- 0.174 · p.Arg175Ser (assay numbering)
- Gene
- TP53
- Assay type
- Not applicable (trained predictor)
- Mechanism
- Loss of function or dominant-negative effect
- Model system
- Not applicable (Not Applicable)
- Score
- 0.0103 · p.Arg175Ser (assay numbering)
Publications
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