rs397516435

chr17-7674945-G-Achr17-7674945-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000546.6(TP53):c.586C>T(p.Arg196Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 2.23

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7674945-G-A is Pathogenic according to our data. Variant chr17-7674945-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 43589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7674945-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.586C>T	p.Arg196Ter	stop_gained	6/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.586C>T	p.Arg196Ter	stop_gained	6/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: decreased DNA binding and transactivation of p53 targets, loss of growth suppression activity (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25757876, 10519380, 24696321, 22187033, 26787237, 28573494, 32504368, 33840814, 29922827, 34282142, 31721094, 17567834, 21761402, 21552135, 23894400, 20128691, 20805372, 25617798, 26425688, 25773284, 25412846, 11479205, 15381368, 19468865, 23580068, 18555592, 8080050, 10226610, 10567903, 12124823, 16322298, 27226433, 28091804, 27501770, 28177947, 29076966, 29979965, 29489754, 30709875, 30268473, 28991257, 30720243, 30730459, 7978053, 31105275, 30982232, 32817165, 31958074, 32368696, 33084842, 33674644, 34863587, 35974385, 35441217, 35418818, 25525159) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2017	The TP53 c.586C>T, p.Arg196Ter variant (rs397516435) has been reported in multiple individuals diagnosed with Li-Fraumeni syndrome (Bendig 2004, Grayson 1994, Vahteristo 2001, Villani 2016). It is observed in the Genome Aggregation Database general population database at a frequency of 0.00041 percent. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Bendig I et al. Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet. 2004; 154(1):22-6. Grayson G et al. Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. Am J Pediatr Hematol Oncol. 1994; 16(4):341-7. Vahteristo P et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001; 61(15):5718-22. Villani A et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016; 17(9):1295-305. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2018	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2022	The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 586. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in a number of individuals with early onset or multiple cancers and in some families who meet either classic diagnostic criteria or Chompret criteria for Li-Fraumeni syndrome (LFS) (Vahteristo P et al. Cancer Research. 2001 Aug;61:5718-5722; Pinto C et al. Fam. Cancer 2009 May;8:383-90; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Mitchell G et al. PLoS One. 2013 Jul;8(7):e69026; Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305; Saya S et al. Fam Cancer. 2017 Jul;16(3):433-440). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 08, 2020	This variant changes 1 nucleotide in exon 6 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 11479205, 19468865), suspected Li-Fraumeni syndrome (PMID: 28573494), childhood adrenal cortical carcinoma (PMID: 7978053) and adult-onset sarcoma (PMID 23894400). This variant has also been observed de novo in an individual affected with rhabdomyosarcoma (PMID: 15381368) This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	-	- -

Li-Fraumeni syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2018	The p.Arg196X variant in TP53 has been reported in >10 individuals with Li-Fraum eni syndrome, with a de novo occurrence in at least 1 individual, and segregated with disease in 1 affected relative from 1 family (Grayson 1994, Vahteristo 200 1, Bendig 2004, Trkova 2007, Pinto 2009, Masciari 2011, Mitchell 2013, Meric-Ber nstam 2016, Villani 2016, LMM data). It has also been identified in 1/111706 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs397516435); however this frequency is low enough to be consistent with the frequency of Li-Fraumeni syndrome in the general population. This nonsense variant leads to a premature termination codon at position 196, w hich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals wi th Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/A MP criteria applied: PVS1, PM2, PM6. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Arg196*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is present in population databases (rs397516435, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 7978053, 11479205, 15381368, 19468865, 21552135, 23894400). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43589). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 15, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

not specified Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

University Health Network, Princess Margaret Cancer Centre

Mar 19, 2021

- -

Adrenocortical carcinoma, hereditary Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 17, 2023

- -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.96
GERP RS		4.4

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: rs397516435; hg19: chr17-7578263; COSMIC: COSV52663748; COSMIC: COSV52663748;