17-7674892-T-C

Variant names:

• chr17-7674892-T-C
• rs1800372
• NM_000546.6:c.639A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000546.6(TP53):​c.639A>G​(p.Arg213Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,614,122 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R213R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 33)
  • Exomes 𝑓: 0.015 (186 hom.)
• Consequence: TP53 NM_000546.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: -3.23
• Publications: 111 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-7674892-T-C is Benign according to our data. Variant chr17-7674892-T-C is described in ClinVar as Benign. ClinVar VariationId is 43591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0125 (1904/152238) while in subpopulation AMR AF = 0.0201 (307/15284). AF 95% confidence interval is 0.0182. There are 20 homozygotes in GnomAd4. There are 867 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1904 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.639A>G	p.Arg213Arg	synonymous_variant	Exon 6 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.639A>G	p.Arg213Arg	synonymous_variant	Exon 6 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1904 AN: 152120 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0126 AC: 3163 AN: 251468 AF XY: 0.0127

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00457

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0146 AC: 21360 AN: 1461884 Hom.: 186 Cov.: 35 AF XY: 0.0145 AC XY: 10512 AN XY: 727242

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.0139 AC: 620 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 899 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00231 AC: 199 AN: 86256

European-Finnish (FIN) AF: 0.00492 AC: 263 AN: 53420

Middle Eastern (MID) AF: 0.0342 AC: 197 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18125 AN: 1112004

Other (OTH) AF: 0.0161 AC: 970 AN: 60396

GnomAD4 genome AF: 0.0125 AC: 1904 AN: 152238 Hom.: 20 Cov.: 33 AF XY: 0.0116 AC XY: 867 AN XY: 74438

African (AFR) AF: 0.00325 AC: 135 AN: 41546

American (AMR) AF: 0.0201 AC: 307 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10610

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1207 AN: 68004

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0166 Hom.: 40

Bravo AF: 0.0137

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0211

EpiControl AF: 0.0232

ClinVar

Significance: Benign

Submissions summary: Benign:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1 Benign:7

Jul 10, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2023

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2016

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 12, 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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:5

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

This variant is associated with the following publications: (PMID: 31748977, 30796655, 27957778, 29979965, 25896519) -

Hereditary cancer-predisposing syndrome Benign:4

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Dec 08, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 p.Arg213= variant was identified in 13 of 844 proband chromosomes (frequency: 0.02) from individuals or families with breast, ovarian, gastric or non-small cell lung cancer (Arcand 2015, Juvan 2007 17436385, Palacio-Rua 2014, Deben 2017). The variant was identified in dbSNP (rs1800372) as “with other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics, Color and 8 other submitters; and as likely benign by Illumina and True Health Diagnostics) and LOVD 3.0 (observed 9x). The variant was identified in control databases in 3407 of 277,174 chromosomes (33 homozygous) at a frequency of 0.01, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 67 of 24,030 chromosomes (freq: 0.003), Other in 126 of 6466 chromosomes (freq: 0.02), Latino in 455 of 34,418 chromosomes (freq: 0.01), European in 2209 of 126,676 chromosomes (freq: 0.02), Ashkenazi Jewish in 343 of 10,152 chromosomes (freq: 0.03), East Asian in 2 of 18,866 chromosomes (freq: 0.0001), Finnish in 119 of 25,784 chromosomes (freq: 0.005), and South Asian in 86 of 30,782 chromosomes (freq: 0.003). The p.Arg213= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs at a non-conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.9
DANN	Benign	0.69
PhyloP100		-3.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800372; hg19: chr17-7578210; COSMIC: COSV52679610; COSMIC: COSV52679610;