TP53 p.Arg273Pro

Variant names:

• chr17-7673802-C-G
• rs28934576
• NM_000546.6:c.818G>C
• TP53 p.Arg273Pro

Your query was ambiguous. Multiple possible variants found:

• chr17-7673802-C-G
• chr17-7673801-AC-CG
• chr17-7673801-AC-GG
• chr17-7673801-AC-TG

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 15 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Strong

The NM_000546.6(TP53):c.818G>C (p.Arg273Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000241, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000274797: Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8" and additional evidence is available in 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) 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): 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 Uncertain Significance, associated with Li-fraumeni syndrome 1 (lfs1); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91
• Publications: 3007 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 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

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 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000274797: Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Canadillas J et al. Proc. Natl. Acad. Sci. U.S.A. 2006 Feb;103(7):2109-14).; SCV000629874: Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20516128, 22484423).; SCV004932602: Functional studies indicate this variant impacts protein function [PMID: 7651740, 8649776, 29979965].
	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		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000241 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	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)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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	NM_000546.6	MANE Select	c.818G>C	p.Arg273Pro	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.818G>C	p.Arg273Pro	missense	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.818G>C	p.Arg273Pro	missense	Exon 9 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.818G>C	p.Arg273Pro	missense	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.818G>C	p.Arg273Pro	missense	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.701G>C	p.Arg234Pro	missense	Exon 7 of 10	ENSP00000478219.1	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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:152054	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome Warning	AF: 0.00000658	AC:1	Hom:0	AN:152054	Cov:31
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:339192	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Li-Fraumeni syndrome 1 (2)
1	-	-	Li-Fraumeni syndrome (1)
1	-	-	not provided (1)
1	-	-	Ovarian neoplasm (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	31
AlphaMissense	Pathogenic	-	1.0
BayesDel_addAF	Pathogenic	D	0.58
BayesDel_noAF	Pathogenic	-	0.59
CADD	Pathogenic	-	26
DANN	Uncertain	-	1.0
DEOGEN2	Pathogenic	D	0.87
Eigen	Uncertain	-	0.68
Eigen_PC	Uncertain	-	0.54
FATHMM_MKL	Pathogenic	D	1.0
FuncVEP CTI	Pathogenic	-	0.99
GPN-Star LLR	N/A	-	-10
GPN-Star score	N/A	-	10
LIST_S2	Benign	T	0.82
M_CAP	Pathogenic	D	0.65
MetaRNN	Pathogenic	D	0.99
MetaSVM	Pathogenic	D	0.93
Mutation Taster	N/A	disease causing (ClinVar)	0/100
MutationAssessor	Pathogenic	M	3.2
PhyloP100	Pathogenic	-	7.9
popEVE	Uncertain	-	-4.6
PrimateAI	Uncertain	T	0.69
PromoterAI	N/A	Neutral	0.0048
PROVEAN	Pathogenic	D	-6.5
REVEL	Pathogenic	-	0.93
Sift	Pathogenic	D	0.0
Sift4G	Pathogenic	D	0.0010
Varity_R	N/A	-	0.99
VESM-3B	Benign	-	-15

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs28934576;

hg19: chr17-7577120;

COSMIC: COSV52676050;

COSMIC: COSV52676050;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar