VCV000664392.13 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (4)

5 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely oncogenic

This classification is based on the single submission received

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.

Functional data are available for this variant

Variant Details

Identifiers

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

Variation ID: 664392 Accession: VCV000664392.13

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	Aug 14, 2019	Jul 19, 2026	May 13, 2026
Somatic - Oncogenicity	Aug 11, 2024	Mar 11, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.375+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000546.4:c.375+1G>C
NM_001126112.3:c.375+1G>C		splice donor
NM_001126113.3:c.375+1G>C		splice donor
NM_001126114.3:c.375+1G>C		splice donor
NM_001126118.2:c.258+1G>C		splice donor
NM_001276695.3:c.258+1G>C		splice donor
NM_001276696.3:c.258+1G>C		splice donor
NM_001276760.3:c.258+1G>C		splice donor
NM_001276761.3:c.258+1G>C		splice donor
NM_001407262.1:c.375+1G>C		splice donor
NM_001407263.1:c.258+1G>C		splice donor
NM_001407264.1:c.375+1G>C		splice donor
NM_001407265.1:c.258+1G>C		splice donor
NM_001407266.1:c.375+1G>C		splice donor
NM_001407267.1:c.258+1G>C		splice donor
NM_001407268.1:c.375+1G>C		splice donor
NM_001407269.1:c.258+1G>C		splice donor
NM_001407270.1:c.375+1G>C		splice donor
NM_001407271.1:c.258+1G>C		splice donor
NC_000017.11:g.7675993C>G
NC_000017.10:g.7579311C>G
NG_017013.2:g.16558G>C
LRG_321:g.16558G>C
LRG_321t1:c.375+1G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:7675992:C:G

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: CA397844135 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	3918	4019

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	Apr 15, 2024	RCV000822481.8
Hereditary cancer-predisposing syndrome	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 13, 2026	RCV002256548.5
Li-Fraumeni syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Jun 18, 2022	RCV002290471.2

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (May 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary cancer-predisposing syndrome	Sema4, Sema4 Accession: SCV002530452.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The TP53 c.375+1G>C variant has not been reported in the literature to our knowledge. This variant is predicted to abolish the canonical splice site leading … (more) The TP53 c.375+1G>C variant has not been reported in the literature to our knowledge. This variant is predicted to abolish the canonical splice site leading to an abnormal or absent protein. This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 664392). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)	Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Genome-Nilou Lab Accession: SCV002582403.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Li-Fraumeni syndrome 1	Genome-Nilou Lab Accession: SCV002583064.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Apr 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Li-Fraumeni syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000963287.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 16199547‚ 20522432‚ 28681140‚ 7887414 Comment: show 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Li-Fraumeni syndrome (PMID: 7887414, 28681140; Invitae). ClinVar contains an entry for this variant (Variation ID: 664392). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (May 13, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV007631990.1 First in ClinVar: Jul 19, 2026 Last updated: Jul 19, 2026	Publications: PubMed (1) PubMed: 28681140 Comment: show The c.375+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 3 of the TP53 gene. Variants that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. A resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; although, direct evidence is unavailable. However, the region predicted to be impacted is critical for protein function and a significant portion of the protein is predicted to be impacted (Ambry internal data). Other variant(s) impacting the same donor site (c.375+2T>G) have been identified in individual(s) with features consistent with Li-Fraumeni syndrome (Azzollini J et al. Fam Cancer, 2018 Jul;17:317-319; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Li-Fraumeni syndrome (PMID: 7887414, 28681140; Invitae). ClinVar contains an entry for this variant (Variation ID: 664392). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.375+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 3 of the TP53 gene. Variants that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. A resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; although, direct evidence is unavailable. However, the region predicted to be impacted is critical for protein function and a significant portion of the protein is predicted to be impacted (Ambry internal data). Other variant(s) impacting the same donor site (c.375+2T>G) have been identified in individual(s) with features consistent with Li-Fraumeni syndrome (Azzollini J et al. Fam Cancer, 2018 Jul;17:317-319; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Increased access to TP53 analysis through breast cancer multi-gene panels: clinical considerations.	Azzollini J	Familial cancer	2018	PMID: 28681140
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
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

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		Likely oncogenic criteria provided, single submitter	Mar 4, 2025	RCV004669145.2

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.	Expand all rows 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.

Likely oncogenic (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)	Neoplasm	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005094460.2 First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

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.

Submissions - Functional Data

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion (p=0.0),junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0)

Modifies a natural donor site at NC_000017.10:g.7579311 from 4.10 to -14.54 bits. Significant p-values: junction spanning - intron inclusion (185 reads, p=0.0), junction spanning - intron inclusion with mutation (2 reads, p=0.0), read abundance - intron inclusion (538 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006902805.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-25-1324), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Ovarian serous cystadenocarcinoma
Transcript: NM_000546.6:c.375+1G>C
Molecular phenotype measured: splicing
Cell line: TCGA-25-1324
Tissue: Ovarian Cancer (OV)
Collection method: in vitro
Species: human
Number of controls: 418

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 Jul 27, 2026