NM_000546.6(TP53):c.641A>G (p.His214Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 14, 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:: RCV000492372.10

Allele description [Variation Report for NM_000546.6(TP53):c.641A>G (p.His214Arg)]

NM_000546.6(TP53):c.641A>G (p.His214Arg)

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.641A>G (p.His214Arg)

HGVS:

NC_000017.11:g.7674890T>C
NG_017013.2:g.17661A>G
NM_000546.6:c.641A>GMANE SELECT
NM_001126112.3:c.641A>G
NM_001126113.3:c.641A>G
NM_001126114.3:c.641A>G
NM_001126115.2:c.245A>G
NM_001126116.2:c.245A>G
NM_001126117.2:c.245A>G
NM_001126118.2:c.524A>G
NM_001276695.3:c.524A>G
NM_001276696.3:c.524A>G
NM_001276697.3:c.164A>G
NM_001276698.3:c.164A>G
NM_001276699.3:c.164A>G
NM_001276760.3:c.524A>G
NM_001276761.3:c.524A>G
NP_000537.3:p.His214Arg
NP_000537.3:p.His214Arg
NP_001119584.1:p.His214Arg
NP_001119585.1:p.His214Arg
NP_001119586.1:p.His214Arg
NP_001119587.1:p.His82Arg
NP_001119588.1:p.His82Arg
NP_001119589.1:p.His82Arg
NP_001119590.1:p.His175Arg
NP_001263624.1:p.His175Arg
NP_001263625.1:p.His175Arg
NP_001263626.1:p.His55Arg
NP_001263627.1:p.His55Arg
NP_001263628.1:p.His55Arg
NP_001263689.1:p.His175Arg
NP_001263690.1:p.His175Arg
LRG_321t1:c.641A>G
LRG_321:g.17661A>G
LRG_321p1:p.His214Arg
NC_000017.10:g.7578208T>C
NM_000546.4:c.641A>G
NM_000546.5(TP53):c.641A>G
NM_000546.5:c.641A>G
p.His214Arg

Protein change:

H175R

Links:

dbSNP: rs1057519992

NCBI 1000 Genomes Browser:

rs1057519992

Molecular consequence:

NM_000546.6:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.245A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.245A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.245A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.524A>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
SCV000581129	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 17, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10761705, 11920959, 20407015, 20522432, 29979965, 30224644, 7732013, 9290701, 9546439 Citation Link,
SCV001358774	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12826609, 20407015, 20522432, 29979965, 30224644, 35033608, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581129

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 17, 2020)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV001358774

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 14, 2022)

germline

clinical testing

PubMed (7)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

p53 status in multiple human urothelial cancers: assessment for clonality by the yeast p53 functional assay in combination with p53 immunohistochemistry.

Yamamoto S, Tada M, Lee CC, Masuda C, Wanibuchi H, Yoshimura R, Wada S, Yamamoto K, Kishimoto T, Fukushima S.

Jpn J Cancer Res. 2000 Feb;91(2):181-9.

PubMed [citation]

PMID:: 10761705
PMCID:: PMC5926329

Complex functions of mutant p53 alleles from human prostate cancer.

Shi XB, Nesslinger NJ, Deitch AD, Gumerlock PH, deVere White RW.

Prostate. 2002 Apr 1;51(1):59-72.

PubMed [citation]

PMID:: 11920959

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000581129.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.H214R pathogenic mutation (also known as c.641A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 641. The histidine at codon 214 is replaced by arginine, an amino acid with highly similar properties. This variant was detected in an individual meeting Chompret criteria with breast cancer at 35, brain cancer at 40, and adrenocortical carcinoma at 41 (Ruijs MW et al. J. Med. Genet. 2010 Jun; 47(6):421-8). 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; Yamamoto S et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):181-9; Flaman JM et al. Oncogene 1998 Mar; 16(10):1369-72). 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 amino acid position is highly conserved through mammals on sequence alignment. 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 Color Diagnostics, LLC DBA Color Health, SCV001358774.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces histidine with arginine at codon 214 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant results in protein that is non-functional in yeast transactivation assays (PMID: 12826609, 20407015), human cell growth suppression assays (PMID: 30224644), and human cell proliferation assay (PMID: 29979965). This variant has been reported in a 41 year old Dutch individual affected with Li Fraumeni-like syndrome meeting Chompret criteria (PMID: 20522432) and a 3 year old Chinese individual affected with glioma (PMID: 35033608). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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

Last Updated: May 25, 2025

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