VCV000093323.17 - ClinVar

NM_000546.6(TP53):c.892G>T (p.Glu298Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

6 conditions

Reviewed by expert panel

Pathogenic

Aug 2024 by ClinGen TP53 V… FDA Recognized Database

for Li-Fraumeni syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_000546.6(TP53):c.892G>T (p.Glu298Ter)

Variation ID: 93323 Accession: VCV000093323.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673728 (GRCh38) [ NCBI UCSC ] 17: 7577046 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 29, 2015	Aug 18, 2024	Aug 5, 2024
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.892G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Glu298Ter	nonsense
NM_000546.5(TP53):c.892G>T
NM_001126112.3:c.892G>T	NP_001119584.1:p.Glu298Ter	nonsense
NM_001126113.3:c.892G>T	NP_001119585.1:p.Glu298Ter	nonsense
NM_001126114.3:c.892G>T	NP_001119586.1:p.Glu298Ter	nonsense
NM_001126115.2:c.496G>T	NP_001119587.1:p.Glu166Ter	nonsense
NM_001126116.2:c.496G>T	NP_001119588.1:p.Glu166Ter	nonsense
NM_001126117.2:c.496G>T	NP_001119589.1:p.Glu166Ter	nonsense
NM_001126118.2:c.775G>T	NP_001119590.1:p.Glu259Ter	nonsense
NM_001276695.3:c.775G>T	NP_001263624.1:p.Glu259Ter	nonsense
NM_001276696.3:c.775G>T	NP_001263625.1:p.Glu259Ter	nonsense
NM_001276697.3:c.415G>T	NP_001263626.1:p.Glu139Ter	nonsense
NM_001276698.3:c.415G>T	NP_001263627.1:p.Glu139Ter	nonsense
NM_001276699.3:c.415G>T	NP_001263628.1:p.Glu139Ter	nonsense
NM_001276760.3:c.775G>T	NP_001263689.1:p.Glu259Ter	nonsense
NM_001276761.3:c.775G>T	NP_001263690.1:p.Glu259Ter	nonsense
NC_000017.11:g.7673728C>A
NC_000017.10:g.7577046C>A
NG_017013.2:g.18823G>T
LRG_321:g.18823G>T
LRG_321t1:c.892G>T	LRG_321p1:p.Glu298Ter

... more HGVS ... less HGVS

Protein change

E166*, E259*, E298*, E139*

Other names

Canonical SPDI

NC_000017.11:7673727:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA000484 dbSNP: rs201744589 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TP53		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3367	3466

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2012	RCV000079204.7
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 22, 2022	RCV000216964.3
Li-Fraumeni syndrome	Pathogenic (2)	reviewed by expert panel	Aug 5, 2024	RCV000559898.7
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785528.2
Rhabdomyosarcoma	Pathogenic (1)	no assertion criteria provided	Sep 1, 2020	RCV001257516.1
Li-Fraumeni syndrome 1	Pathogenic (1)	criteria provided, single submitter	Feb 21, 2024	RCV004019532.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 05, 2024)	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0) Method: curation	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen TP53 Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV001142557.2 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/42caf4f2-7ef5-45d4-a593-271e92b9ca88 Comment: The NM_000546.6 c.892G>T (p.Glu298Ter) is a TP53 nonsense variant inducing a premature termination codon upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay … (more) The NM_000546.6 c.892G>T (p.Glu298Ter) is a TP53 nonsense variant inducing a premature termination codon upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1). This variant has been observed in 1 family meeting Revised Chompret criteria. This proband was under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: SCV000278127.7). At least one individual with this variant was found to have a variant allele fraction 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, SCV000278127.7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024) (less)
Pathogenic (Sep 07, 2012)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111074.8 First in ClinVar: Jan 23, 2014 Last updated: Jun 29, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TP53 Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Oct 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000629883.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 20522432‚ 12610779‚ 21305319 Comment: This sequence change creates a premature translational stop signal (p.Glu298) in the TP53 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Glu298) 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: 12610779, 21305319). ClinVar contains an entry for this variant (Variation ID: 93323). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 21, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004933100.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Feb 22, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000278127.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 12610779‚ 21305319 Comment: The p.E298* pathogenic mutation (also known as c.892G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at … (more) The p.E298* pathogenic mutation (also known as c.892G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 892. This changes the amino acid from a glutamic acid to a stop codon within coding exon 7. This alteration was detected in a large Li-Fraumeni kindred consisting of 33 carriers of the alteration and a total of 32 tumors (Wu CC et al. Hum. Genet. 2011 Jun; 129(6):663-73). 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. (less)
Pathogenic (Sep 01, 2020)	no assertion criteria provided Method: provider interpretation	Rhabdomyosarcoma Affected status: yes Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434342.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020
Pathogenic (Dec 01, 2018)	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: somatic	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000924100.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019

Comment:

The NM_000546.6 c.892G>T (p.Glu298Ter) is a TP53 nonsense variant inducing a premature termination codon upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1). This variant has been observed in 1 family meeting Revised Chompret criteria. This proband was under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: SCV000278127.7). At least one individual with this variant was found to have a variant allele fraction 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, SCV000278127.7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024)

Comment:

This sequence change creates a premature translational stop signal (p.Glu298*) 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: 12610779, 21305319). ClinVar contains an entry for this variant (Variation ID: 93323). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.E298* pathogenic mutation (also known as c.892G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 892. This changes the amino acid from a glutamic acid to a stop codon within coding exon 7. This alteration was detected in a large Li-Fraumeni kindred consisting of 33 carriers of the alteration and a total of 32 tumors (Wu CC et al. Hum. Genet. 2011 Jun; 129(6):663-73). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.	Li H	Journal of the National Cancer Institute	2021	PMID: 33372952
Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome.	Wu CC	Human genetics	2011	PMID: 21305319
TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.	Ruijs MW	Journal of medical genetics	2010	PMID: 20522432
Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.	Hwang SJ	American journal of human genetics	2003	PMID: 12610779
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TP53	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/42caf4f2-7ef5-45d4-a593-271e92b9ca88	-	-	-	-

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668772.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094381.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs201744589 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.892G>T (p.Glu298Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs201744589 ...