VCV000406610.6 - ClinVar

NM_000546.6(TP53):c.920-1G>C

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.

(2)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.920-1G>C

Variation ID: 406610 Accession: VCV000406610.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673609 (GRCh38) [ NCBI UCSC ] 17: 7576927 (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	Apr 17, 2017	Feb 28, 2024	Oct 28, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.920-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001126112.3:c.920-1G>C		splice acceptor
NM_001126113.3:c.920-1G>C		splice acceptor
NM_001126114.3:c.920-1G>C		splice acceptor
NM_001126115.2:c.524-1G>C		splice acceptor
NM_001126116.2:c.524-1G>C		splice acceptor
NM_001126117.2:c.524-1G>C		splice acceptor
NM_001126118.2:c.803-1G>C		splice acceptor
NM_001276695.3:c.803-1G>C		splice acceptor
NM_001276696.3:c.803-1G>C		splice acceptor
NM_001276697.3:c.443-1G>C		splice acceptor
NM_001276698.3:c.443-1G>C		splice acceptor
NM_001276699.3:c.443-1G>C		splice acceptor
NM_001276760.3:c.803-1G>C		splice acceptor
NM_001276761.3:c.803-1G>C		splice acceptor
NM_001407262.1:c.920-1G>C		splice acceptor
NM_001407263.1:c.803-1G>C		splice acceptor
NM_001407264.1:c.920-1G>C		splice acceptor
NM_001407265.1:c.803-1G>C		splice acceptor
NM_001407266.1:c.920-1G>C		splice acceptor
NM_001407267.1:c.803-1G>C		splice acceptor
NM_001407268.1:c.920-1G>C		splice acceptor
NM_001407269.1:c.803-1G>C		splice acceptor
NM_001407270.1:c.920-1G>C		splice acceptor
NM_001407271.1:c.803-1G>C		splice acceptor
NC_000017.11:g.7673609C>G
NC_000017.10:g.7576927C>G
NG_017013.2:g.18942G>C
LRG_321:g.18942G>C
LRG_321t1:c.920-1G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:7673608:C:G

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

ClinGen: CA16615686 dbSNP: rs587781702 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	Oct 28, 2022	RCV000458070.5
not provided	Likely pathogenic (1)	no assertion criteria provided	Mar 7, 2022	RCV003151060.2

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 (Oct 28, 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: SCV000545362.5 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 19556618‚ 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: 406610). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 19556618; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 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 (Mar 07, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV003840136.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: DNA sequence analysis of the TP53 gene demonstrated a sequence change in the canonical splice acceptor site of intron 8, c.920-1G>C. This sequence change has … (more) DNA sequence analysis of the TP53 gene demonstrated a sequence change in the canonical splice acceptor site of intron 8, c.920-1G>C. This sequence change has not been described in population databases such as ExAC and gnomAD. Based on in-silico splice prediction programs, this sequence change likely affects normal splicing of the TP53 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. Although this sequence change does not appear to have been previously described in individuals with TP53-related disorders, two different variants affecting the same position, c.920-1G>A and c.920-1G>T, have been reported in individuals with Li-Fraumeni syndrome or in individuals with tumors belonging to the Li-Fraumeni syndrome tumor spectrum (PMID: 21305319, 19556618, 21305319, 31105275). Based on these collective evidences, this sequence change is classified as likely pathogenic; clinical correlation is recommended. (less)

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: 406610). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 19556618; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 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:

DNA sequence analysis of the TP53 gene demonstrated a sequence change in the canonical splice acceptor site of intron 8, c.920-1G>C. This sequence change has not been described in population databases such as ExAC and gnomAD. Based on in-silico splice prediction programs, this sequence change likely affects normal splicing of the TP53 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. Although this sequence change does not appear to have been previously described in individuals with TP53-related disorders, two different variants affecting the same position, c.920-1G>A and c.920-1G>T, have been reported in individuals with Li-Fraumeni syndrome or in individuals with tumors belonging to the Li-Fraumeni syndrome tumor spectrum (PMID: 21305319, 19556618, 21305319, 31105275). Based on these collective evidences, this sequence change is classified as likely pathogenic; clinical correlation is recommended.

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
High frequency of de novo mutations in Li-Fraumeni syndrome.	Gonzalez KD	Journal of medical genetics	2009	PMID: 19556618
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs587781702 ...

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.920-1G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587781702 ...