rs201744589

Variant names:

• chr17-7673728-C-A
• rs201744589
• NM_000546.6:c.892G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7673728-C-A
• chr17-7673728-C-G
• chr17-7673728-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PS4_Supporting PP4 PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000546.6 c.892G>T (p.Glu298Ter) is a TP53 nonsense variant inducing a premature termination codon upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1). This variant has been observed in 1 family meeting Revised Chompret criteria. This proband was under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: SCV000278127.7). At least one individual with this variant was found to have a variant allele fraction 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID:34906512, SCV000278127.7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000484/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: -0.746
• Publications: 171 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.892G>T	p.Glu298*	stop_gained	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.892G>T	p.Glu298*	stop_gained	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.892G>T	p.Glu298*	stop_gained	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.892G>T	p.Glu298*	stop_gained	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.892G>T	p.Glu298*	stop_gained	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.775G>T	p.Glu259*	stop_gained	Exon 7 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Li-Fraumeni syndrome (3)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Li-Fraumeni syndrome 1 (1)
1	-	-	Ovarian neoplasm (1)
1	-	-	Rhabdomyosarcoma (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Benign	0.87
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.36	N
PhyloP100		-0.75
Vest4		0.74
GERP RS		-4.0
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201744589; hg19: chr17-7577046; COSMIC: COSV52661551; COSMIC: COSV52661551;