NM_000546.6(TP53):c.749C>T (p.Pro250Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001026502.3

Allele description [Variation Report for NM_000546.6(TP53):c.749C>T (p.Pro250Leu)]

NM_000546.6(TP53):c.749C>T (p.Pro250Leu)

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.749C>T (p.Pro250Leu)

HGVS:

NC_000017.11:g.7674214G>A
NG_017013.2:g.18337C>T
NM_000546.6:c.749C>TMANE SELECT
NM_001126112.3:c.749C>T
NM_001126113.3:c.749C>T
NM_001126114.3:c.749C>T
NM_001126115.2:c.353C>T
NM_001126116.2:c.353C>T
NM_001126117.2:c.353C>T
NM_001126118.2:c.632C>T
NM_001276695.3:c.632C>T
NM_001276696.3:c.632C>T
NM_001276697.3:c.272C>T
NM_001276698.3:c.272C>T
NM_001276699.3:c.272C>T
NM_001276760.3:c.632C>T
NM_001276761.3:c.632C>T
NP_000537.3:p.Pro250Leu
NP_000537.3:p.Pro250Leu
NP_001119584.1:p.Pro250Leu
NP_001119585.1:p.Pro250Leu
NP_001119586.1:p.Pro250Leu
NP_001119587.1:p.Pro118Leu
NP_001119588.1:p.Pro118Leu
NP_001119589.1:p.Pro118Leu
NP_001119590.1:p.Pro211Leu
NP_001263624.1:p.Pro211Leu
NP_001263625.1:p.Pro211Leu
NP_001263626.1:p.Pro91Leu
NP_001263627.1:p.Pro91Leu
NP_001263628.1:p.Pro91Leu
NP_001263689.1:p.Pro211Leu
NP_001263690.1:p.Pro211Leu
LRG_321t1:c.749C>T
LRG_321:g.18337C>T
LRG_321p1:p.Pro250Leu
NC_000017.10:g.7577532G>A
NM_000546.4:c.749C>T
NM_000546.5:c.749C>T

Protein change:

P118L

Links:

dbSNP: rs1064794311

Molecular consequence:

NM_000546.6:c.749C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.749C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.749C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.749C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.353C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.353C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.353C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.632C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.632C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.632C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.272C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.272C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.272C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.632C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.632C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001188897	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11429705, 12826609, 30224644, 30607672 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001188897

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 17, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements.

Campomenosi P, Monti P, Aprile A, Abbondandolo A, Frebourg T, Gold B, Crook T, Inga A, Resnick MA, Iggo R, Fronza G.

Oncogene. 2001 Jun 14;20(27):3573-9.

PubMed [citation]

PMID:: 11429705

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001188897.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.P250L pathogenic mutation (also known as c.749C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 749. The proline at codon 250 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an individual with a personal history of breast cancer diagnosed at age 30 (Bakhuizen JJ et al. Fam Cancer, 2019 Apr;18:273-280). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays. (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9). Additional studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Apr 12, 2026

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