NM_000546.6(TP53):c.581T>G (p.Leu194Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 25, 2024
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:: RCV000561306.4

Allele description [Variation Report for NM_000546.6(TP53):c.581T>G (p.Leu194Arg)]

NM_000546.6(TP53):c.581T>G (p.Leu194Arg)

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.581T>G (p.Leu194Arg)

HGVS:

NC_000017.11:g.7674950A>C
NG_017013.2:g.17601T>G
NM_000546.6:c.581T>GMANE SELECT
NM_001126112.3:c.581T>G
NM_001126113.3:c.581T>G
NM_001126114.3:c.581T>G
NM_001126115.2:c.185T>G
NM_001126116.2:c.185T>G
NM_001126117.2:c.185T>G
NM_001126118.2:c.464T>G
NM_001276695.3:c.464T>G
NM_001276696.3:c.464T>G
NM_001276697.3:c.104T>G
NM_001276698.3:c.104T>G
NM_001276699.3:c.104T>G
NM_001276760.3:c.464T>G
NM_001276761.3:c.464T>G
NP_000537.3:p.Leu194Arg
NP_000537.3:p.Leu194Arg
NP_001119584.1:p.Leu194Arg
NP_001119585.1:p.Leu194Arg
NP_001119586.1:p.Leu194Arg
NP_001119587.1:p.Leu62Arg
NP_001119588.1:p.Leu62Arg
NP_001119589.1:p.Leu62Arg
NP_001119590.1:p.Leu155Arg
NP_001263624.1:p.Leu155Arg
NP_001263625.1:p.Leu155Arg
NP_001263626.1:p.Leu35Arg
NP_001263627.1:p.Leu35Arg
NP_001263628.1:p.Leu35Arg
NP_001263689.1:p.Leu155Arg
NP_001263690.1:p.Leu155Arg
LRG_321t1:c.581T>G
LRG_321:g.17601T>G
LRG_321p1:p.Leu194Arg
NC_000017.10:g.7578268A>C
NM_000546.4:c.581T>G
NM_000546.5:c.581T>G

Protein change:

L155R

Links:

dbSNP: rs1057519998

NCBI 1000 Genomes Browser:

rs1057519998

Molecular consequence:

NM_000546.6:c.581T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.581T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.581T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.581T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.185T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.185T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.185T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.464T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.464T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.464T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.464T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.464T>G - 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
SCV000676299	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 29979965, 30224644 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000676299

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 25, 2024)

germline

clinical testing

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

Citation Link

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

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

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000676299.6

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

Description

The p.L194R variant (also known as c.581T>G), located in coding exon 5 of the TP53 gene, results from a T to G substitution at nucleotide position 581. The leucine at codon 194 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of 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 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 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. 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

Last Updated: May 16, 2025

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