chr17-7675209-A-C

Variant names:

• chr17-7675209-A-C
• rs1057519975
• ENST00000619186.4:c.-75T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PS3 PM1_Supporting PP3_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.403T>G variant in TP53 is a missense variant predicted to cause substitution of Cysteine by Glycine at amino acid 135 (p.Cys135Gly). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, Internal lab contributors: SCV000664432.4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMID:12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5991; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID:30311369) (PM1_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: PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1_Supporting. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602989/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_001276697.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.32
• Publications: 243 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, 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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276697.3. 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.403T>G	p.Cys135Gly	missense	Exon 5 of 11	NP_000537.3
	TP53	NM_001276697.3		c.-75T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001263626.1
	TP53	NM_001276699.3		c.-75T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001263628.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000619186.4	TSL:1	c.-75T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000484375.1
	TP53	ENST00000610623.4	TSL:1	c.-75T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000477531.1
	TP53	ENST00000618944.4	TSL:1	c.-75T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000481401.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Li-Fraumeni syndrome (1)
1	-	-	Li-Fraumeni syndrome 1 (1)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.85		Loss of ubiquitination at K139 (P = 0.0675)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		1.0
gMVP		0.81
Mutation Taster		=2/98	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: rs1057519975; hg19: chr17-7578527; COSMIC: COSV52827707; COSMIC: COSV52827707;