NM_000546.6(TP53):c.749C>T (p.Pro250Leu) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 9, 2018
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:: RCV000479937.2

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568759	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (May 9, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568759

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(May 9, 2018)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000568759.3

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

Description

This variant is denoted TP53 c.749C>T at the cDNA level, p.Pro250Leu (P250L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has been reported as a somatic variant in osteosarcoma, rhabdomyosarcoma, chronic lymphocytic leukemia, and other tumors and cell lines, but has not been reported as a germline variant to our knowledge (Toguchida 1992, Gokgoz 2001, Pekova 2011, COSMIC). TP53 Pro250Leu is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and has also been described as demonstrating reduced or absent transactivation capabilities in other studies (Campomenosi 2001, Maurici 2001, Monti 2002). In addition, this variant was shown to cause cytoplasmic protein aggregation, resulting in impaired nuclear import and destabilization in HT-1376 bladder cells (Xu 2011). TP53 Pro250Leu was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Pro250Leu to be a likely pathogenic variant.

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

Last Updated: Apr 12, 2026

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