rs730882029

chr17-7670685-G-Achr17-7670685-G-Cchr17-7670685-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000546.6(TP53):c.1024C>T(p.Arg342Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R342R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 1.17

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7670685-G-A is Pathogenic according to our data. Variant chr17-7670685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 182970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7670685-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1024C>T	p.Arg342Ter	stop_gained	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1024C>T	p.Arg342Ter	stop_gained	10/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 31, 2022	PVS1, PM1, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2018	The TP53 c.1024C>T; p.Arg342Ter variant (rs730882029) is reported in the germline of at least two individuals with suspected Li Fraumeni syndrome (Hettmer 2014, Trkova 2007). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 182970), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: Hettmer S et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014 Apr 1;120(7):1068-75. Trkova M et al. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007 Aug 1;110(3):694-702. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19714490, 28693246, 34249677, 35016432, 24382691, 26425688, 21761402, 20436704, 10519380, 12779080, 18555592, 9115587, 21190917, 16969106, 12509970, 21665182, 28408749, 23484829, 17567834, 28526081, 18511570, 19556618, 26911350, 19711436, 30720243, 31081129, 31105275, 31447099, 32817165, 31742824, 33294277) -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2022	The p.R342* pathogenic mutation (also known as c.1024C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1024. This changes the amino acid from an arginine to a stop codon within coding exon 9. In one study, this mutation was detected in a 5-year-old male diagnosed with an adrenocortical tumor at 1.5 years of age and a medulloblastoma at 5 years of age. His 31-year-old unaffected father was also a carrier of the mutation (Trkova et al. Cancer. 2007 Aug;110(3):694-702). In another study, this alteration was identified in a 4-year-old who had been diagnosed with osteosarcoma, adenocarcinoma, and anaplastic rhabdomyosarcoma (Hettmer S et al. Cancer 2014 Apr;120(7):1068-75). It has also been reported in patients and/or families with breast and/or ovarian cancer (Melhem-Bertrandt A et al. Cancer 2012 Feb;118:908-13; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	curation	Sema4, Sema4	Mar 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 11, 2021	This variant changes 1 nucleotide in exon 10 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown the mutant protein to be mis-localized and unable to activate downstream targets (PMID: 16969106). This variant has been reported in multiple individuals affected with Li-Fraumeni syndrome-associated cancer, including childhood onset adrenocarcinoma, brain tumor and soft-tissue sarcoma (PMID: 17567834, 19711436, 19714490, 19556618, 24382691) and adult-onset breast and/or ovarian cancer (PMID: 21761402, 26911350). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Li-Fraumeni syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change creates a premature translational stop signal (p.Arg342*) 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: 17567834, 19714490, 21761402, 24382691, 26911350). ClinVar contains an entry for this variant (Variation ID: 182970). 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	Apr 20, 2018	The p.Arg342X variant in TP53 has been reported as a germline variant in more th an 15 individuals with TP53-associated cancers and as a somatic variant in more than 100 individuals (Fiszer-Maliszewska 2009, Schniederjan 2009, Lee 2010, Melh em-Bertrandt 2012, Hettmer 2014, Kandioler 2015, Mannan 2016, Smardova 2016, IAR C TP53 database [http://p53.iarc.fr/], COSMIC database). This variant has also b een reported in ClinVar (Variation ID# 182970) and was absent from large populat ion studies. In vitro functional studies provide some evidence that the p.Arg342 X variant may impact protein function by resulting in abnormal nuclear localizat ion (Trostel 2006). This nonsense variant leads to a premature termination codon at position 342 which is predicted to lead to a truncated or absent protein. He terozygous loss of function of the TP53 gene is an established disease mechanism in Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifi ed as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based upon frequency in affected individuals, absence from controls, and the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PS4; PM2; PS3_Supportin g. -

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 21, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 28, 2022

- -

Colonic diverticula Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 09, 2021

- -

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

- -

Fabry disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 25, 2024

Variant summary: GLA c.1024C>T (p.Arg342X) 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 (eg. ***). The variant was absent in 182951 control chromosomes. c.1024C>T has been reported in the literature in individuals affected with Fabry Disease. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Two 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

Gallbladder cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Oct 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A;A;N;N;N;N
Vest4		0.87
GERP RS		3.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8

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: rs730882029; hg19: chr17-7574003; COSMIC: COSV52665487; COSMIC: COSV52665487;