17-7675074-C-T

Variant names:

• chr17-7675074-C-T
• rs879253911
• NM_000546.6:c.538G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3_Moderate PM2_Supporting PS4 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.538G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 180 (p.Glu180Lys). This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.262; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4; PM2_Supporting, PS3_Moderate; PP3. (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584590/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.03
• Publications: 58 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: 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.
• PP3: 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.538G>A	p.Glu180Lys	missense	Exon 5 of 11	NP_000537.3
	TP53	NM_001126112.3		c.538G>A	p.Glu180Lys	missense	Exon 5 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.538G>A	p.Glu180Lys	missense	Exon 6 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.538G>A	p.Glu180Lys	missense	Exon 5 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.538G>A	p.Glu180Lys	missense	Exon 5 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.421G>A	p.Glu141Lys	missense	Exon 4 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Li-Fraumeni syndrome (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
1	-	-	TP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PhyloP100		5.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.90		Gain of ubiquitination at E180 (P = 0.0104)
MVP		0.94
MPC		1.8
ClinPred		0.97	D
GERP RS		5.5
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.42
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs879253911; hg19: chr17-7578392; COSMIC: COSV52816009; COSMIC: COSV52816009;