Genetic Variant TP53:p.Arg273Leu (chr17-7673801-ACG-CAA) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5

The NM_000546.6(TP53):c.817_819delCGTinsTTG (p.Arg273Leu) 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. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). 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.R273C: Pathogenic/Likely_pathogenic (ClinVar VariationId 43594, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R273?: Uncertain_significance (ClinVar VariationId 2055104, 1 star); p.R273= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 619925) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. The variant position is a cancer hotspot (cancerhotspots.org): 862 samples carry this exact amino acid change out of 6034 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Li-fraumeni syndrome 1 (lfs1); it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 31)

Consequence

TP53
NM_000546.6 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

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 cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Li-Fraumeni syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
Li-Fraumeni syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
adrenocortical carcinoma, hereditary
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
bone marrow failure syndrome 5
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
colorectal cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
choroid plexus carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TP53 links:

Genome browser will be placed here

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: Pathogenic. The variant received 14 points.

Show applied only (4)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 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: 63 pathogenic, 3 benign (OR vs. background: 90.7).
	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.R273C: Pathogenic/Likely_pathogenic (ClinVar VariationId 43594, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R273?: Uncertain_significance (ClinVar VariationId 2055104, 1 star); p.R273= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 619925)

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

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TP53 NM_000546.6	MANE Select	c.817_819delCGTinsTTG p.Arg273Leu	missense	N/A	Prot: NP_000537.3
TP53 NM_001126112.3		c.817_819delCGTinsTTG p.Arg273Leu	missense	N/A	Prot: NP_001119584.1 UniProt: K7PPA8P04637-1
TP53 NM_001407262.1		c.817_819delCGTinsTTG p.Arg273Leu	missense	N/A	Prot: NP_001394191.1 UniProt: K7PPA8P04637-1

TP53 NM_000546.6

MANE Select

HGVSc / HGVSpc.817_819delCGTinsTTGp.Arg273Leu

Exon rankN/A

missense

Prot: NP_000537.3

TP53 NM_001126112.3

HGVSc / HGVSpc.817_819delCGTinsTTGp.Arg273Leu

Exon rankN/A

missense

Prot: NP_001119584.1UniProt: K7PPA8

P04637-1

TP53 NM_001407262.1

HGVSc / HGVSpc.817_819delCGTinsTTGp.Arg273Leu

Exon rankN/A

missense

Prot: NP_001394191.1UniProt: K7PPA8

P04637-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TP53 ENST00000269305.9	TSL:1MANE Select	c.817_819delCGTinsTTG p.Arg273Leu	missense	N/A	Prot: ENSP00000269305.4 UniProt: P04637-1
TP53 ENST00000445888.6	TSL:1	c.817_819delCGTinsTTG p.Arg273Leu	missense	N/A	Prot: ENSP00000391478.2 UniProt: P04637-1
TP53 ENST00000610292.4	TSL:1	c.700_702delCGTinsTTG p.Arg234Leu	missense	N/A	Prot: ENSP00000478219.1 UniProt: P04637-4

TP53 ENST00000269305.9

TSL:1MANE Select

HGVSc / HGVSpc.817_819delCGTinsTTGp.Arg273Leu

Exon rankN/A

missense

Prot: ENSP00000269305.4UniProt: P04637-1

TP53 ENST00000445888.6

TSL:1

HGVSc / HGVSpc.817_819delCGTinsTTGp.Arg273Leu

Exon rankN/A

missense

Prot: ENSP00000391478.2UniProt: P04637-1

TP53 ENST00000610292.4

TSL:1

HGVSc / HGVSpc.700_702delCGTinsTTGp.Arg234Leu

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 Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

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 spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 abnormal

13 abnormal (RUO)

1 no calibration

15 assays found for this variant.

Clinical calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).

Research-use-only (RUO) calibration: 13 functionally abnormal (PS3), 0 functionally normal (BS3).

No calibration: 1 assay (score only).

RUO results are not validated; give them no weight next to the clinical ones.

Protein level

Mutated p53 paired with wildtype under nutlin-3

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: 1.35 · p.Arg273Leu (assay numbering)

Protein level

Mutated p53 with nutlin-3

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: 0.664 · p.Arg273Leu (assay numbering)

Protein level

Combined score using three assays of TP53 activity that assess loss of function or dominant negative effect

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: 0.967 · p.Arg273Leu (assay numbering)

Protein level

Mutated p53 with etoposide

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: -0.891 · p.Arg273Leu (assay numbering)