Genetic Variant TP53:p.Arg273Leu (chr17-7673801-AC-GA) – 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.818_819delGTinsTC (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.

PS1

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).

PM1

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).

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

PM5

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.818_819delGTinsTC	p.Arg273Leu	missense	N/A	NP_000537.3
TP53	NM_001126112.3		c.818_819delGTinsTC	p.Arg273Leu	missense	N/A	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.818_819delGTinsTC	p.Arg273Leu	missense	N/A	NP_001394191.1	K7PPA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53	ENST00000269305.9	TSL:1 MANE Select	c.818_819delGTinsTC	p.Arg273Leu	missense	N/A	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.818_819delGTinsTC	p.Arg273Leu	missense	N/A	ENSP00000391478.2	P04637-1
TP53	ENST00000610292.4	TSL:1	c.701_702delGTinsTC	p.Arg234Leu	missense	N/A	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.9

Splicing

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.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over