chr17-7673802-C-A

Variant names:

• chr17-7673802-C-A
• rs28934576
• NM_000546.6:c.818G>T
• TP53 p.Arg273Leu

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>T (p.Arg273Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000147, 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: "SCV000665156: Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9" 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) This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). 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: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:3
• 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.

Our verdict: Pathogenic. The variant received 15 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000665156: Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti, P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth Let al. Carcinogenesis 2007 Feb; 28(2):289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387).; SCV000962866: Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 12826609, 21343334, 29979965, 30224644).; SCV004848115: "In vitro functional studies provide some evidence that the p.Arg273Leu variant may impact protein function (Kawamura 1996, Monti 2011, Ory 1994)."; SCV001757640: Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of apoptotic activity, and exhibits a dominant-negative effect (Monti et al., 2007; Monti et al., 2011; Giacomelli et al., 2018; Kotler et al., 2018)
• 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: Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
• 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)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: 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>T	p.Arg273Leu	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.818G>T	p.Arg273Leu	missense	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.818G>T	p.Arg273Leu	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>T	p.Arg273Leu	missense	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.818G>T	p.Arg273Leu	missense	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.701G>T	p.Arg234Leu	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 6 sources Large-scale international reference populations
GnomAD3 genomes	0.00000658	1	0	152054	31
GnomAD2 exomes	0.00000398	1		251054
GnomAD4 exome Warning	6.84e-7	1	0	1461808	33
GnomAD4 genome Warning	0.00000658	1	0	152054	31
TOPMed (Bravo)	0.00000378
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00	0	0	339192

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Li-Fraumeni syndrome (2)
1	-	-	Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 (1)
1	-	-	Li-Fraumeni syndrome 1 (1)
1	-	-	not provided (1)
1	-	-	Ovarian neoplasm (1)
-	-	-	Embryonal rhabdomyosarcoma (1)
-	-	-	Neoplasm (1)
-	-	-	Neuroendocrine tumor of pancreas (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	Uncertain	-	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	-	1.0
GPN-Star LLR	N/A	-	-9.3
GPN-Star score	N/A	-	9.3
LIST_S2	Benign	D	0.85
M_CAP	Pathogenic	D	0.66
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	Benign	-	-4.5
PrimateAI	Uncertain	T	0.69
PromoterAI	N/A	Neutral	0.0095
PROVEAN	Pathogenic	D	-6.5
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.7
REVEL	Pathogenic	-	0.92
Sift	Pathogenic	D	0.0
Sift4G	Pathogenic	D	0.0010
Varity_R	N/A	-	0.98
VESM-3B	Benign	-	-13

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.010
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.020

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: COSV52664805;

COSMIC: COSV52664805;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar