NM_000546.6(TP53):c.451C>A (p.Pro151Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 21, 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:: RCV000130617.11

Allele description [Variation Report for NM_000546.6(TP53):c.451C>A (p.Pro151Thr)]

NM_000546.6(TP53):c.451C>A (p.Pro151Thr)

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.451C>A (p.Pro151Thr)

HGVS:

NC_000017.11:g.7675161G>T
NG_017013.2:g.17390C>A
NM_000546.6:c.451C>AMANE SELECT
NM_001126112.3:c.451C>A
NM_001126113.3:c.451C>A
NM_001126114.3:c.451C>A
NM_001126115.2:c.55C>A
NM_001126116.2:c.55C>A
NM_001126117.2:c.55C>A
NM_001126118.2:c.334C>A
NM_001276695.3:c.334C>A
NM_001276696.3:c.334C>A
NM_001276697.3:c.-27C>A
NM_001276698.3:c.-27C>A
NM_001276699.3:c.-27C>A
NM_001276760.3:c.334C>A
NM_001276761.3:c.334C>A
NP_000537.3:p.Pro151Thr
NP_000537.3:p.Pro151Thr
NP_001119584.1:p.Pro151Thr
NP_001119585.1:p.Pro151Thr
NP_001119586.1:p.Pro151Thr
NP_001119587.1:p.Pro19Thr
NP_001119588.1:p.Pro19Thr
NP_001119589.1:p.Pro19Thr
NP_001119590.1:p.Pro112Thr
NP_001263624.1:p.Pro112Thr
NP_001263625.1:p.Pro112Thr
NP_001263689.1:p.Pro112Thr
NP_001263690.1:p.Pro112Thr
LRG_321t1:c.451C>A
LRG_321:g.17390C>A
LRG_321p1:p.Pro151Thr
NC_000017.10:g.7578479G>T
NM_000546.4:c.451C>A
NM_000546.5:c.451C>A
P04637:p.Pro151Thr
p.P151T

Protein change:

P112T; PRO151THR

Links:

UniProtKB: P04637#VAR_005896; OMIM: 191170.0025; dbSNP: rs28934874

Molecular consequence:

NM_001276697.3:c.-27C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-27C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-27C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.451C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.451C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.451C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.451C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.55C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.55C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.55C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.334C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.334C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.334C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.334C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.334C>A - 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
SCV000185493	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 21, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11479205, 12826609, 25503501, 29979965, 30224644 Citation Link,
SCV002582396	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185493

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 21, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002582396

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]

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

Citations

PubMed

p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.

Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Aaltonen LA, Blomqvist C, Aittomäki K, Nevanlinna H.

Cancer Res. 2001 Aug 1;61(15):5718-22.

PubMed [citation]

PMID:: 11479205

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 (6)

Details of each submission

From Ambry Genetics, SCV000185493.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.P151T pathogenic mutation (also known as c.451C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 451. The proline at codon 151 is replaced by threonine, an amino acid with highly similar properties. This mutation has been reported in several families meeting clinical criteria for Li-Fraumeni Syndrome (LFS) (Vahteristo P et al. Cancer Res. 2001; 61:5718-22; Ambry internal data). This variant was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). 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 was not reported in population-based 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

From Genome-Nilou Lab, SCV002582396.1

#	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

Last Updated: Apr 12, 2026

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