rs397516436

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000546.6(TP53):c.637C>T(p.Arg213Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R213R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 0.754

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-7674894-G-A is Pathogenic according to our data. Variant chr17-7674894-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 43590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.637C>T	p.Arg213Ter	stop_gained	6/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.637C>T	p.Arg213Ter	stop_gained	6/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152104

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 12, 2023	_x000D_ Criteria applied: PVS1, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
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. -

Li-Fraumeni syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Arg213*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 11479205, 16401470, 16534790, 21552135, 21626334). ClinVar contains an entry for this variant (Variation ID: 43590). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 20, 2013	The Arg213X variant in TP53 has been previously reported in the literature in se veral individuals with features consistent with or a clinical diagnosis of LFS ( Horio 1994, Frebourg 1995, Varley 1999, Vahteristo 2001, Wong 2006, Trahair 2007 , Ferrarini 2011). Varley et al. (1999) also observed loss of heterozygosity for TP53 in an adrenocortical carcinoma tumor from an individual with the germline Arg213X variant. This variant has been well described as a somatic variant in mu ltiple tumor types, including those found as part of LFS (COSMIC). The Arg213X v ariant leads to a premature stop at codon 213. From this DNA sequencing test, we cannot determine the effect this nucleotide change will have on the protein pro duced, but it is predicted to lead to a truncated or absent protein. Therefore, this variant is highly likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2023	Variant summary: TP53 c.637C>T (p.Arg213X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251460 control chromosomes. c.637C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and related conditions with co-segregation evidence (Example: Frebourg_1995, Trahair_2007, Masciari_2011 etc.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. A section of an NSCLC with the variant was negative for TP53 staining, suggesting the transcript is a target for nonsense mediated decay (Hashimoto_1999). Another report shows severe decrease in DNA binding (Malcikova_2010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2022	The p.R213* pathogenic mutation (also known as c.637C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 637. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has previously been reported in an affected individual from a family meeting classic Li-Fraumeni syndrome criteria (Wong P et al. Gastroenterology. 2006 Jan;130(1):73-9). This mutation has also been reported in patients with gastric cancer, breast cancer and medulloblastoma (Horio Y et al. Oncogene. 1994 Apr;9(4):1231-5; Momota H et al. Pediatr. Blood Cancer. 2010 Sep;55(3):577-9; Masciari S et al. Genet. Med. 2011 Jul;13(7):651-7; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164(3):593-601; Waszak SM et al. Lancet Oncol. 2018 Jun;19(6):785-798). In addition this mutation was shown to result in loss of DNA binding compared to wild-type (Malcikova J et al. Biol. Chem. 2010 Feb-Mar;391(2-3):197-205). 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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	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: loss of DNA binding and growth suppression activities (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 11479205, 25525159, 15656799, 24803582, 30309854, 10486318, 28056804, 29655027, 27059324, 29489754, 20128691, 8134126, 21552135, 20658636, 21626334, 22203015, 15099937, 7887414, 16401470, 24220311, 23334668, 24702488, 26681312, 15902285, 28503720, 29351612, 29979965, 30412573, 29354595, 29700339, 29076966, 21225465, 27146902, 26425688, 9667734, 20522432, 29753700, 30720243, 31278746, 27535533, 31105275, 32000721, 30816478) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2022	This nonsense variant causes the premature termination of TP53 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (PMID: 21552135 (2011)), colorectal cancer (PMID: 26425688 (2015), 32000721 (2020)), breast cancer (PMID: 32994724 (2020), 28503720 (2017), 26681312 (2015)), and ovarian cancer (PMID: 27059324 (2016)). The variant has also been reported in individuals with glioma (PMID: 31278746 (2019)) and medulloblastoma (PMID: 29753700 (2018), 29489754 (2018). Based on the available information, this variant is classified as pathogenic. -

Familial cancer of breast

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	University Health Network, Princess Margaret Cancer Centre	Mar 19, 2021	- -
Pathogenic, criteria provided, single submitter	case-control	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	-	- -

Colorectal cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.43

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

A;A;A;A;A;A

Vest4

0.99

GERP RS

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.47

Position offset: -35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over