VCV000640648.11 - ClinVar

NM_000546.6(TP53):c.801dup (p.Asn268fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline 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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

Clinical impact

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP 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 somatic clinical impact 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.

Tier IV (Benign)/Likely benign for Chronic myelogenous leukemia, BCR-ABL1 positive

no assertion criteria provided

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.801dup (p.Asn268fs)

Variation ID: 640648 Accession: VCV000640648.11

Type and length

Duplication, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673818-7673819 (GRCh38) [ NCBI UCSC ] 17: 7577136-7577137 (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	Aug 14, 2019	May 1, 2024	Jun 18, 2022
Somatic - Clinical impact	Jun 17, 2024	Jun 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.799_800insG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000546.6:c.801dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Asn268fs	frameshift
NM_000546.5:c.801dupG
NM_001126112.3:c.801dup	NP_001119584.1:p.Asn268fs	frameshift
NM_001126113.3:c.801dup	NP_001119585.1:p.Asn268fs	frameshift
NM_001126114.3:c.801dup	NP_001119586.1:p.Asn268fs	frameshift
NM_001126115.2:c.405dup	NP_001119587.1:p.Asn136fs	frameshift
NM_001126116.2:c.405dup	NP_001119588.1:p.Asn136fs	frameshift
NM_001126117.2:c.405dup	NP_001119589.1:p.Asn136fs	frameshift
NM_001126118.2:c.684dup	NP_001119590.1:p.Asn229fs	frameshift
NM_001276695.3:c.684dup	NP_001263624.1:p.Asn229fs	frameshift
NM_001276696.3:c.684dup	NP_001263625.1:p.Asn229fs	frameshift
NM_001276697.3:c.324dup	NP_001263626.1:p.Asn109fs	frameshift
NM_001276698.3:c.324dup	NP_001263627.1:p.Asn109fs	frameshift
NM_001276699.3:c.324dup	NP_001263628.1:p.Asn109fs	frameshift
NM_001276760.3:c.684dup	NP_001263689.1:p.Asn229fs	frameshift
NM_001276761.3:c.684dup	NP_001263690.1:p.Asn229fs	frameshift
NC_000017.11:g.7673820dup
NC_000017.10:g.7577138dup
NG_017013.2:g.18732dup
LRG_321:g.18732dup

... more HGVS ... less HGVS

Protein change

N268fs, N229fs, N136fs, N109fs

Other names

Canonical SPDI

NC_000017.11:7673818:CC:CCC

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.

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

Links

dbSNP: rs1597362206 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.
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 28, 2018	RCV000793717.6
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 18, 2022	RCV001027071.5
Li-Fraumeni syndrome 1	Pathogenic (1)	criteria provided, single submitter	Jun 18, 2022	RCV002290433.2

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 (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582455.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002583117.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Jul 28, 2018)	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: SCV000933084.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 20522432 Comment: For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant has not … (more) For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant has not been reported in the literature in individuals with TP53-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn268Glufs*4) in the TP53 gene. It is expected to result in an absent or disrupted protein product. (less)
Pathogenic (Jul 31, 2018)	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: SCV001189573.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The c.801dupG pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a duplication of G at nucleotide position 801, causing a … (more) The c.801dupG pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a duplication of G at nucleotide position 801, causing a translational frameshift with a predicted alternate stop codon (p.N268Efs*4). 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)

Comment:

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant has not been reported in the literature in individuals with TP53-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn268Glufs*4) in the TP53 gene. It is expected to result in an absent or disrupted protein product.

Comment:

The c.801dupG pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a duplication of G at nucleotide position 801, causing a translational frameshift with a predicted alternate stop codon (p.N268Efs*4). 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.

Comment:

Classified as Benign/likely benign based on the presence of de novo mutation in a patient with clinical features consistent with CML. Functional studies (Soverini et al., 2015, PMID: 26297264) demonstrated that mutation in the Tp53 gene relates to the loss of function of the protein. Classification follows ACMG/AMP guidelines, meeting criteria PS2 (de novo occurrence), PS3 (functional evidence), and PM2 (absence in controls).

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
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

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.
Chronic myelogenous leukemia, BCR-ABL1 positive	Tier IV (Benign)/Likely benign (1)		-	RCV004576968.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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.

Tier IV (Benign)/Likely benign

(-)

Method: research

Chronic myelogenous leukemia, BCR-ABL1 positive

Affected status: unknown

Allele origin: somatic

Molecular Biology (Zoology) Lab, University of Education, Lahore

Accession: SCV005061368.1
First In ClinVar: Jun 17, 2024
Last updated: Jun 17, 2024

Comment:

Classified as Benign/likely benign based on the presence of de novo mutation in a patient with clinical features consistent with CML. Functional studies (Soverini et … (more)

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 rs1597362206 ...

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.801dup (p.Asn268fs)

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 rs1597362206 ...