VCV000635393.33 - ClinVar

NM_000546.6(TP53):c.375+1G>T

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.

(7)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000546.6(TP53):c.373_375+1delinsCCTT

Identifiers

NM_000546.6(TP53):c.375+1G>T

Variation ID: 635393 Accession: VCV000635393.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7675993 (GRCh38) [ NCBI UCSC ] 17: 7579311 (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	Jul 6, 2019	Oct 20, 2024	Aug 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.375+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001126112.3:c.375+1G>T		splice donor
NM_001126113.3:c.375+1G>T		splice donor
NM_001126114.3:c.375+1G>T		splice donor
NM_001126118.2:c.258+1G>T		splice donor
NM_001276695.3:c.258+1G>T		splice donor
NM_001276696.3:c.258+1G>T		splice donor
NM_001276760.3:c.258+1G>T		splice donor
NM_001276761.3:c.258+1G>T		splice donor
NM_001407262.1:c.375+1G>T		splice donor
NM_001407263.1:c.258+1G>T		splice donor
NM_001407264.1:c.375+1G>T		splice donor
NM_001407265.1:c.258+1G>T		splice donor
NM_001407266.1:c.375+1G>T		splice donor
NM_001407267.1:c.258+1G>T		splice donor
NM_001407268.1:c.375+1G>T		splice donor
NM_001407269.1:c.258+1G>T		splice donor
NM_001407270.1:c.375+1G>T		splice donor
NM_001407271.1:c.258+1G>T		splice donor
NC_000017.11:g.7675993C>A
NC_000017.10:g.7579311C>A
NG_017013.2:g.16558G>T
LRG_321:g.16558G>T
LRG_321t1:c.375+1G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:7675992:C:A

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

sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]

Intron inclusion between exons 4 & 5, based on review of RNA-seq in KMS-27 cancer cell line which has TP53 NM_000546.5:c.375+1G>T variant. [submitted by MutSpliceDB: a database of splice sites variants effects on splicing, NIH]

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: rs1567555445 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 (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2022	RCV000786840.23
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 16, 2022	RCV000804919.7
Hereditary cancer-predisposing syndrome	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 18, 2022	RCV001021045.4
Li-Fraumeni syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Jun 18, 2022	RCV002290035.1

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 (Oct 17, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001805078.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Canonical splice site variant predicted to result in an in-frame deletion of a critical region: disrupts the transactivation domain, nuclear export signals, SH3 domain, and … (more) Canonical splice site variant predicted to result in an in-frame deletion of a critical region: disrupts the transactivation domain, nuclear export signals, SH3 domain, and DNA binding domain (Zhang 2001, Bode 2004, Pessoa 2014); Published functional studies demonstrate a damaging effect: aberrant splicing (Smardova 2016); Not observed in large population cohorts (Lek 2016); Identified in patients with personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx; A different variant affecting the same splice site (c.375G>A) has been reported as pathogenic at GeneDx in association with Li-Fraumeni syndrome and shown to result in a similar splicing impact (Varley 2001, Bougeard 2008, Hettmer 2014, Wasserman 2015); This variant is associated with the following publications: (PMID: 26718964, 28807936) (less)
Likely 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: SCV002582404.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Likely 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: SCV002583065.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Aug 16, 2022)	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: SCV000944857.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 7887414‚ 17224268‚ 16199547‚ 20522432 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 635393). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 17224268; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). (less)
Likely pathogenic (Apr 06, 2021)	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: SCV001182608.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The c.375+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 3 of the TP53 gene. This nucleotide position is … (more) The c.375+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 3 of the TP53 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002498240.18 First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
not provided (-)	no classification provided Method: in vitro	not provided Affected status: not applicable Allele origin: not applicable	MutSpliceDB: a database of splice sites variants effects on splicing, NIH Accession: SCV000925736.2 First in ClinVar: Jul 06, 2019 Last updated: Jul 06, 2019	Other databases https://brb.nci.nih.gov/cgi-bin/… https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA397844143 Method: Based on review of RNA-seq data in sample with variant. Result: Intron inclusion between exons 4 & 5

Comment:

Canonical splice site variant predicted to result in an in-frame deletion of a critical region: disrupts the transactivation domain, nuclear export signals, SH3 domain, and DNA binding domain (Zhang 2001, Bode 2004, Pessoa 2014); Published functional studies demonstrate a damaging effect: aberrant splicing (Smardova 2016); Not observed in large population cohorts (Lek 2016); Identified in patients with personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx; A different variant affecting the same splice site (c.375G>A) has been reported as pathogenic at GeneDx in association with Li-Fraumeni syndrome and shown to result in a similar splicing impact (Varley 2001, Bougeard 2008, Hettmer 2014, Wasserman 2015); This variant is associated with the following publications: (PMID: 26718964, 28807936)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 635393). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 17224268; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432).

Comment:

The c.375+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 3 of the TP53 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
sequence_variant_affecting_splicing (SO:1000071)	Based on review of RNA-seq data in sample with variant.	Intron inclusion between exons 4 & 5	MutSpliceDB: a database of splice sites variants effects on splicing, NIH Accession: SCV000925736.2	Other databases https://brb.nci.nih.gov/cgi-bin/… Comment: Intron inclusion between exons 4 & 5, based on review of RNA-seq in KMS-27 cancer cell line which has TP53 NM_000546.5:c.375+1G>T variant.

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
Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families.	Manoukian S	European journal of cancer (Oxford, England : 1990)	2007	PMID: 17224268
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome.	Frebourg T	American journal of human genetics	1995	PMID: 7887414
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA397844143	-	-	-	-

Text-mined citations for rs1567555445 ...

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.375+1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1567555445 ...