chr17-7675519-A-G

Variant names:

• chr17-7675519-A-G
• rs1794287
• NM_000546.6:c.376-283T>C

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.376-283T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 706,784 control chromosomes in the GnomAD database, including 269,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54820 hom., cov: 28)
  • Exomes 𝑓: 0.88 (214665 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.876
• Publications: 13 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=-0.98).
• BP6: Variant 17-7675519-A-G is Benign according to our data. Variant chr17-7675519-A-G is described in ClinVar as Benign. ClinVar VariationId is 695142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.376-283T>C		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.376-283T>C		intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.376-283T>C		intron	N/A	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.376-283T>C		intron	N/A	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.376-283T>C		intron	N/A	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.259-283T>C		intron	N/A	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128473 AN: 151628 Hom.: 54781 Cov.: 28

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.893

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.850

GnomAD4 exome AF: 0.878 AC: 487272 AN: 555038 Hom.: 214665 Cov.: 8 AF XY: 0.874 AC XY: 247866 AN XY: 283574

African (AFR) AF: 0.738 AC: 10688 AN: 14480

American (AMR) AF: 0.915 AC: 14837 AN: 16216

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 10953 AN: 13030

East Asian (EAS) AF: 0.973 AC: 25054 AN: 25746

South Asian (SAS) AF: 0.803 AC: 36949 AN: 46002

European-Finnish (FIN) AF: 0.895 AC: 18193 AN: 20322

Middle Eastern (MID) AF: 0.767 AC: 1535 AN: 2002

European-Non Finnish (NFE) AF: 0.886 AC: 344914 AN: 389454

Other (OTH) AF: 0.869 AC: 24149 AN: 27786

GnomAD4 genome AF: 0.847 AC: 128559 AN: 151746 Hom.: 54820 Cov.: 28 AF XY: 0.846 AC XY: 62790 AN XY: 74190

African (AFR) AF: 0.744 AC: 30698 AN: 41264

American (AMR) AF: 0.893 AC: 13590 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2942 AN: 3462

East Asian (EAS) AF: 0.967 AC: 4985 AN: 5156

South Asian (SAS) AF: 0.807 AC: 3881 AN: 4808

European-Finnish (FIN) AF: 0.893 AC: 9432 AN: 10566

Middle Eastern (MID) AF: 0.710 AC: 206 AN: 290

European-Non Finnish (NFE) AF: 0.887 AC: 60254 AN: 67960

Other (OTH) AF: 0.851 AC: 1796 AN: 2110

Alfa AF: 0.846 Hom.: 3139

Bravo AF: 0.845

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20127977)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Li-Fraumeni syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Li-Fraumeni syndrome 1 Benign:1

Jun 18, 2022

Genome-Nilou Lab

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.64
DANN	Benign	0.55
PhyloP100		-0.88
PromoterAI		0.010	Neutral
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: rs1794287; hg19: chr17-7578837;