NM_000546.6(TP53):c.375+1G>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: May 13, 2026
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002256548.5

Allele description [Variation Report for NM_000546.6(TP53):c.375+1G>C]

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

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

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

HGVS:

NC_000017.11:g.7675993C>G
NG_017013.2:g.16558G>C
NM_000546.6:c.375+1G>CMANE SELECT
NM_001126112.3:c.375+1G>C
NM_001126113.3:c.375+1G>C
NM_001126114.3:c.375+1G>C
NM_001126118.2:c.258+1G>C
NM_001276695.3:c.258+1G>C
NM_001276696.3:c.258+1G>C
NM_001276760.3:c.258+1G>C
NM_001276761.3:c.258+1G>C
NM_001407262.1:c.375+1G>C
NM_001407263.1:c.258+1G>C
NM_001407264.1:c.375+1G>C
NM_001407265.1:c.258+1G>C
NM_001407266.1:c.375+1G>C
NM_001407267.1:c.258+1G>C
NM_001407268.1:c.375+1G>C
NM_001407269.1:c.258+1G>C
NM_001407270.1:c.375+1G>C
NM_001407271.1:c.258+1G>C
LRG_321t1:c.375+1G>C
LRG_321:g.16558G>C
NC_000017.10:g.7579311C>G
NM_000546.4:c.375+1G>C
NM_000546.5:c.375+1G>C

Links:

dbSNP: rs1567555445

Molecular consequence:

NM_000546.6:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126112.3:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126113.3:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126114.3:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126118.2:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276695.3:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276696.3:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276760.3:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276761.3:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407262.1:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407263.1:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407264.1:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407265.1:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407266.1:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407267.1:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407268.1:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407269.1:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407270.1:c.375+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407271.1:c.258+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002530452	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (May 6, 2021)	germline	curation	Citation Link,
SCV002582403	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007631990	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 13, 2026)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002530452

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(May 6, 2021)

germline

curation

Citation Link,

SCV002582403

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 18, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV007631990

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 13, 2026)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Increased access to TP53 analysis through breast cancer multi-gene panels: clinical considerations.

Azzollini J, Mariani M, Peissel B, Manoukian S.

Fam Cancer. 2018 Jul;17(3):317-319. doi: 10.1007/s10689-017-0020-z. No abstract available.

PubMed [citation]

PMID:: 28681140
PMCID:: PMC5999151

Details of each submission

From Sema4, Sema4, SCV002530452.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002582403.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV007631990.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 27, 2026

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