17-7668783-C-T

Variant names:

• chr17-7668783-C-T
• rs17884306
• NM_000546.6:c.*826G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000546.6(TP53):​c.*826G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 223,876 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (268 hom., cov: 30)
  • Exomes 𝑓: 0.048 (100 hom.)
• Consequence: TP53 NM_000546.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.390
• Publications: 27 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-7668783-C-T is Benign according to our data. Variant chr17-7668783-C-T is described in ClinVar as Benign. ClinVar VariationId is 325623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.*826G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.*826G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0516 AC: 7572 AN: 146758 Hom.: 264 Cov.: 30

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0500

Gnomad EAS AF: 0.0713

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.00667

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0420

GnomAD4 exome AF: 0.0479 AC: 3692 AN: 77010 Hom.: 100 Cov.: 0 AF XY: 0.0484 AC XY: 1724 AN XY: 35588

African (AFR) AF: 0.0274 AC: 98 AN: 3580

American (AMR) AF: 0.0374 AC: 88 AN: 2354

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 232 AN: 4858

East Asian (EAS) AF: 0.0599 AC: 656 AN: 10948

South Asian (SAS) AF: 0.0912 AC: 60 AN: 658

European-Finnish (FIN) AF: 0.0357 AC: 8 AN: 224

Middle Eastern (MID) AF: 0.0148 AC: 7 AN: 472

European-Non Finnish (NFE) AF: 0.0471 AC: 2241 AN: 47572

Other (OTH) AF: 0.0476 AC: 302 AN: 6344

GnomAD4 genome AF: 0.0518 AC: 7603 AN: 146866 Hom.: 268 Cov.: 30 AF XY: 0.0546 AC XY: 3883 AN XY: 71146

African (AFR) AF: 0.0287 AC: 1132 AN: 39410

American (AMR) AF: 0.0455 AC: 655 AN: 14390

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 173 AN: 3460

East Asian (EAS) AF: 0.0719 AC: 361 AN: 5022

South Asian (SAS) AF: 0.0753 AC: 353 AN: 4690

European-Finnish (FIN) AF: 0.117 AC: 1085 AN: 9298

Middle Eastern (MID) AF: 0.00714 AC: 2 AN: 280

European-Non Finnish (NFE) AF: 0.0541 AC: 3647 AN: 67420

Other (OTH) AF: 0.0495 AC: 99 AN: 1998

Alfa AF: 0.0555 Hom.: 34

Bravo AF: 0.0456

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.74
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs17884306; hg19: chr17-7572101;