rs1800899

chr17-7673523-A-Gchr17-7673523-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000546.6(TP53):c.993+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,726 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (18 hom., cov: 31)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: -0.437

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-7673523-A-G is Benign according to our data. Variant chr17-7673523-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673523-A-G is described in Lovd as [Benign]. Variant chr17-7673523-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0156 (2381/152248) while in subpopulation AFR AF= 0.0279 (1158/41538). AF 95% confidence interval is 0.0265. There are 18 homozygotes in gnomad4. There are 1076 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.993+12T>C		intron_variant		ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.993+12T>C		intron_variant		1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2376 AN: 152130 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0111 AC: 2797 AN: 251290 Hom.: 21 AF XY: 0.0115 AC XY: 1566 AN XY: 135810

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0132 AC: 19279 AN: 1461478 Hom.: 151 Cov.: 33 AF XY: 0.0130 AC XY: 9432 AN XY: 727060

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0156 AC: 2381 AN: 152248 Hom.: 18 Cov.: 31 AF XY: 0.0145 AC XY: 1076 AN XY: 74450

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0136 Hom.: 8

Bravo AF: 0.0169

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:29

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome Benign:6

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -

Li-Fraumeni syndrome 1 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	This variant is associated with the following publications: (PMID: 30796655, 26270727) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TP53: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Li-Fraumeni syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 19, 2021

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The TP53 c.993+12T>C, variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, LOVD 3.0, IARC TP53 Database, UMD TP52 Mutation Database, Database of germline p53 mutations, databases. The variant was identified in dbSNP (rs: 1800899) “with likely benign allele”, ClinVar (5x as benign and 1x as likely benign) associated with the phenotypes of Li-Fraumeni syndrome and Hereditary cancer-predisposing syndrome, and the Clinvitae database. The variant was identified in control databases in 3159 of 277250 chromosomes at a frequency of 0.011394 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 656 of 24036 chromosomes (freq: 0.027), European (Non-Finnish) in 1750 of 126732 chromosomes (freq: 0.014), South Asian in 321 of 30782 chromosomes (freq: 0.01). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.0
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800899; hg19: chr17-7576841; COSMIC: COSV53015717; COSMIC: COSV53015717;