NM_000546.6(TP53):c.875A>G (p.Lys292Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 31, 2018
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:: RCV000573281.7

Allele description [Variation Report for NM_000546.6(TP53):c.875A>G (p.Lys292Arg)]

NM_000546.6(TP53):c.875A>G (p.Lys292Arg)

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.875A>G (p.Lys292Arg)

Other names:

NM_000546.5(TP53):c.875A>G; p.Lys292Arg

HGVS:

NC_000017.11:g.7673745T>C
NG_017013.2:g.18806A>G
NM_000546.6:c.875A>GMANE SELECT
NM_001126112.3:c.875A>G
NM_001126113.3:c.875A>G
NM_001126114.3:c.875A>G
NM_001126115.2:c.479A>G
NM_001126116.2:c.479A>G
NM_001126117.2:c.479A>G
NM_001126118.2:c.758A>G
NM_001276695.3:c.758A>G
NM_001276696.3:c.758A>G
NM_001276697.3:c.398A>G
NM_001276698.3:c.398A>G
NM_001276699.3:c.398A>G
NM_001276760.3:c.758A>G
NM_001276761.3:c.758A>G
NP_000537.3:p.Lys292Arg
NP_000537.3:p.Lys292Arg
NP_001119584.1:p.Lys292Arg
NP_001119585.1:p.Lys292Arg
NP_001119586.1:p.Lys292Arg
NP_001119587.1:p.Lys160Arg
NP_001119588.1:p.Lys160Arg
NP_001119589.1:p.Lys160Arg
NP_001119590.1:p.Lys253Arg
NP_001263624.1:p.Lys253Arg
NP_001263625.1:p.Lys253Arg
NP_001263626.1:p.Lys133Arg
NP_001263627.1:p.Lys133Arg
NP_001263628.1:p.Lys133Arg
NP_001263689.1:p.Lys253Arg
NP_001263690.1:p.Lys253Arg
LRG_321t1:c.875A>G
LRG_321:g.18806A>G
LRG_321p1:p.Lys292Arg
NC_000017.10:g.7577063T>C
NC_000017.10:g.7577063T>C
NM_000546.4:c.875A>G
NM_000546.5:c.875A>G

Protein change:

K133R

Links:

dbSNP: rs121912663

NCBI 1000 Genomes Browser:

rs121912663

Molecular consequence:

NM_000546.6:c.875A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.875A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.875A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.875A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.758A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.758A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.758A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.398A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.398A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.398A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.758A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.758A>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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Aspergillus kawachii IFO 4308 DNA, contig: scaffold00025, whole genome shotgun s...
Aspergillus kawachii IFO 4308 DNA, contig: scaffold00025, whole genome shotgun sequence
gi|358373340|dbj|DF126471.1|

Nucleotide
JGI_XZT10121.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7588141 5'...
JGI_XZT10121.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7588141 5', mRNA sequence
gi|57045904|gnl|dbEST|26936718|gb|C 54.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000664424	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 29, 2016)	germline	clinical testing	Citation Link,
SCV000910134	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 31, 2018)	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

SCV000664424

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 29, 2016)

germline

clinical testing

Citation Link,

SCV000910134

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 31, 2018)

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000664424.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.K292R variant (also known as c.875A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 875. The lysine at codon 292 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in the functionally critical DNA binding domain, and has been shown to have transactivation capacity similar to wild type in yeast-based functional studies (IARC TP53 database: Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 250000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV000910134.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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