NM_000546.6(TP53):c.452C>G (p.Pro151Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 29, 2024
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:: RCV003168617.4

Allele description [Variation Report for NM_000546.6(TP53):c.452C>G (p.Pro151Arg)]

NM_000546.6(TP53):c.452C>G (p.Pro151Arg)

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.452C>G (p.Pro151Arg)

HGVS:

NC_000017.11:g.7675160G>C
NG_017013.2:g.17391C>G
NM_000546.4:c.452C>G
NM_000546.6:c.452C>GMANE SELECT
NM_001126112.3:c.452C>G
NM_001126113.3:c.452C>G
NM_001126114.3:c.452C>G
NM_001126115.2:c.56C>G
NM_001126116.2:c.56C>G
NM_001126117.2:c.56C>G
NM_001126118.2:c.335C>G
NM_001276695.3:c.335C>G
NM_001276696.3:c.335C>G
NM_001276697.3:c.-26C>G
NM_001276698.3:c.-26C>G
NM_001276699.3:c.-26C>G
NM_001276760.3:c.335C>G
NM_001276761.3:c.335C>G
NP_000537.3:p.Pro151Arg
NP_000537.3:p.Pro151Arg
NP_001119584.1:p.Pro151Arg
NP_001119585.1:p.Pro151Arg
NP_001119586.1:p.Pro151Arg
NP_001119587.1:p.Pro19Arg
NP_001119588.1:p.Pro19Arg
NP_001119589.1:p.Pro19Arg
NP_001119590.1:p.Pro112Arg
NP_001263624.1:p.Pro112Arg
NP_001263625.1:p.Pro112Arg
NP_001263689.1:p.Pro112Arg
NP_001263690.1:p.Pro112Arg
LRG_321t1:c.452C>G
LRG_321:g.17391C>G
LRG_321p1:p.Pro151Arg
NC_000017.10:g.7578478G>C
NM_000546.5:c.452C>G

Protein change:

P112R

Links:

dbSNP: rs1057520000

Molecular consequence:

NM_001276697.3:c.-26C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-26C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-26C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.56C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.56C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.56C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.335C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.335C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.335C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.335C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.335C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV003911993	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 34805717 Citation Link,
SCV005407756	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	criteria provided, single submitter (Fortuno et al. (Hum Mutat. 2021))	Likely pathogenic (Jan 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 30224644, 33300245

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003911993

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 29, 2024)

germline

clinical testing

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

Citation Link,

SCV005407756

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

criteria provided, single submitter

(Fortuno et al. (Hum Mutat. 2021))

Likely pathogenic
(Jan 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013..

PubMed [citation]

PMID:: 29979965

Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome.

Frone MN, Stewart DR, Savage SA, Khincha PP.

JCO Precis Oncol. 2021;5. doi:pii: PO.21.00320. 10.1200/PO.21.00320.

PubMed [citation]

PMID:: 34805717
PMCID:: PMC8594664

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV003911993.2

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

Description

The p.P151R pathogenic mutation (also known as c.452C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 452. The proline at codon 151 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a family meeting Chompret criteria (Frone MN et al. JCO Precis Oncol, 2021 Nov;5:). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

From Molecular Diagnostics Laboratory, Catalan Institute of Oncology, SCV005407756.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

c.452C>G, located in exon 5 of the TP53 gene, is predicted to result in the substitution of Proline by Arginine at codon 151, p.(Pro151Arg). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.49) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At present, there is another pathogenic missense variant in the same residue, c.451C>T, p.(Pro151Ser) (PM5_supporting). It has been reported in ClinVar (1x as pathogenic, 17x as likely pathogenic) and CancerHotspots (9 somatic observations). Based on the currently available information, c.452C>G is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.

#	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	1	not provided

Last Updated: Apr 12, 2026

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