NM_000546.6(TP53):c.451C>T (p.Pro151Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 18, 2022
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:: RCV000219702.15

Allele description [Variation Report for NM_000546.6(TP53):c.451C>T (p.Pro151Ser)]

NM_000546.6(TP53):c.451C>T (p.Pro151Ser)

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>T (p.Pro151Ser)

HGVS:

NC_000017.11:g.7675161G>A
NG_017013.2:g.17390C>T
NM_000546.6:c.451C>TMANE SELECT
NM_001126112.3:c.451C>T
NM_001126113.3:c.451C>T
NM_001126114.3:c.451C>T
NM_001126115.2:c.55C>T
NM_001126116.2:c.55C>T
NM_001126117.2:c.55C>T
NM_001126118.2:c.334C>T
NM_001276695.3:c.334C>T
NM_001276696.3:c.334C>T
NM_001276697.3:c.-27C>T
NM_001276698.3:c.-27C>T
NM_001276699.3:c.-27C>T
NM_001276760.3:c.334C>T
NM_001276761.3:c.334C>T
NP_000537.3:p.Pro151Ser
NP_000537.3:p.Pro151Ser
NP_001119584.1:p.Pro151Ser
NP_001119585.1:p.Pro151Ser
NP_001119586.1:p.Pro151Ser
NP_001119587.1:p.Pro19Ser
NP_001119588.1:p.Pro19Ser
NP_001119589.1:p.Pro19Ser
NP_001119590.1:p.Pro112Ser
NP_001263624.1:p.Pro112Ser
NP_001263625.1:p.Pro112Ser
NP_001263689.1:p.Pro112Ser
NP_001263690.1:p.Pro112Ser
LRG_321t1:c.451C>T
LRG_321:g.17390C>T
LRG_321p1:p.Pro151Ser
NC_000017.10:g.7578479G>A
NM_000546.4:c.451C>T
NM_000546.5:c.451C>T
P04637:p.Pro151Ser

Protein change:

P112S; PRO151SER

Links:

UniProtKB: P04637#VAR_005895; OMIM: 191170.0026; dbSNP: rs28934874

NCBI 1000 Genomes Browser:

rs28934874

Molecular consequence:

NM_001276697.3:c.-27C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-27C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-27C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.55C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.55C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.55C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; 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
SCV000272964	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 24, 2021)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 11479205, 11896595, 11920959, 16861262, 1686725, 20128691, 20522432, 21343334, 23625637, 29324801, 29470806, 29752822, 30630526, 7881428 Citation Link,
SCV002582395	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

SCV000272964

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 24, 2021)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link,

SCV002582395

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	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

Tumour p53 mutations exhibit promoter selective dominance over wild type p53.

Monti P, Campomenosi P, Ciribilli Y, Iannone R, Inga A, Abbondandolo A, Resnick MA, Fronza G.

Oncogene. 2002 Mar 7;21(11):1641-8.

PubMed [citation]

PMID:: 11896595

See all PubMed Citations (15)

Details of each submission

From Ambry Genetics, SCV000272964.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The p.P151S variant (also known as c.451C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 451. The proline at codon 151 is replaced by serine, an amino acid with similar properties. This alteration has been confirmed as de novo in a proband with a personal history of adrenocortical carcinoma diagnosed at 7 months, fibrosarcoma of the scalp diagnosed at age 4, and a right sided retroperitoneal rhabdomyosarcoma diagnosed at age 5 (Gutiérrez MI et al. Hum Mol Genet, 1994 Dec;3:2247-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (Shi XB et al. Prostate. 2002 Apr;51(1):59-72; IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98; Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). A study examining DNA binding in p53 alterations reported that p.P151S exhibited significantly decreased binding compared to wild type p53 (Malcikova J et al. Biol. Chem. 2010 391(2-3):197-205). Another study conducted in tumor cell lines indicates that this alteration may confer resistance to apoptosis. This same group performed structural analysis and concluded that this variant is likely to result in significant conformational changes that are deleterious to the function of the protein (Xie TX et al. Laryngoscope 2013 Jun;123(6):1416-23). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, SCV002582395.1

#	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: Jun 9, 2024

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