17-7676583-C-T

Variant names:

• chr17-7676583-C-T
• rs876658274
• NM_000546.6:c.12G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000546.6(TP53):​c.12G>A​(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TP53 NM_000546.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.88
• Publications: 40 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-7676583-C-T is Benign according to our data. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676583-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 229927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.88 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.12G>A	p.Pro4Pro	synonymous_variant	Exon 2 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.12G>A	p.Pro4Pro	synonymous_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152012 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461774 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152012 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Benign:3

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary cancer-predisposing syndrome Benign:3

Apr 11, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 29, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Li-Fraumeni syndrome Benign:2

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast;C1835398:Li-Fraumeni syndrome 1 Benign:1

Oct 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely 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	-0.77
CADD	Benign	0.69
DANN	Benign	0.70
PhyloP100		-2.9
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876658274; hg19: chr17-7579901;