NM_000546.6(TP53):c.569C>G (p.Pro190Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 14, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000222080.6

Allele description [Variation Report for NM_000546.6(TP53):c.569C>G (p.Pro190Arg)]

NM_000546.6(TP53):c.569C>G (p.Pro190Arg)

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.569C>G (p.Pro190Arg)

HGVS:

NC_000017.11:g.7674962G>C
NG_017013.2:g.17589C>G
NM_000546.6:c.569C>GMANE SELECT
NM_001126112.3:c.569C>G
NM_001126113.3:c.569C>G
NM_001126114.3:c.569C>G
NM_001126115.2:c.173C>G
NM_001126116.2:c.173C>G
NM_001126117.2:c.173C>G
NM_001126118.2:c.452C>G
NM_001276695.3:c.452C>G
NM_001276696.3:c.452C>G
NM_001276697.3:c.92C>G
NM_001276698.3:c.92C>G
NM_001276699.3:c.92C>G
NM_001276760.3:c.452C>G
NM_001276761.3:c.452C>G
NP_000537.3:p.Pro190Arg
NP_000537.3:p.Pro190Arg
NP_001119584.1:p.Pro190Arg
NP_001119585.1:p.Pro190Arg
NP_001119586.1:p.Pro190Arg
NP_001119587.1:p.Pro58Arg
NP_001119588.1:p.Pro58Arg
NP_001119589.1:p.Pro58Arg
NP_001119590.1:p.Pro151Arg
NP_001263624.1:p.Pro151Arg
NP_001263625.1:p.Pro151Arg
NP_001263626.1:p.Pro31Arg
NP_001263627.1:p.Pro31Arg
NP_001263628.1:p.Pro31Arg
NP_001263689.1:p.Pro151Arg
NP_001263690.1:p.Pro151Arg
LRG_321t1:c.569C>G
LRG_321:g.17589C>G
LRG_321p1:p.Pro190Arg
NC_000017.10:g.7578280G>C
NM_000546.4:c.569C>G
NM_000546.5:c.569C>G
P04637:p.Pro190Arg

Protein change:

P151R

Links:

UniProtKB: P04637#VAR_044981; dbSNP: rs876660825

NCBI 1000 Genomes Browser:

rs876660825

Molecular consequence:

NM_000546.6:c.569C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.569C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.569C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.569C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.173C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.173C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.173C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.452C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.452C>G - 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
SCV000278552	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 12909720, 26787237, 28499267 Citation Link,
SCV002582056	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (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

SCV000278552

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 14, 2022)

germline

clinical testing

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

Citation Link,

SCV002582056

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(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

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

Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity.

Resnick MA, Inga A.

Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9934-9. Epub 2003 Aug 8.

PubMed [citation]

PMID:: 12909720
PMCID:: PMC187891

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000278552.8

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

Description

The p.P190R variant (also known as c.569C>G), located in coding exon 5 of the TP53 gene, results from a C to G substitution at nucleotide position 569. The proline at codon 190 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in an individual meeting Chompret criteria (Krzeniak M et al. Adv Med Sci, 2017 Sep;62:207-210) and has also been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, P190R is more disruptive to the DNA-binding domain of TP53 than nearby pathogenic variants (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic.

#	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, SCV002582056.1

#	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: Sep 29, 2024

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