NM_000546.6(TP53):c.646G>A (p.Val216Met) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 25, 2019
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:: RCV000161067.9

Allele description [Variation Report for NM_000546.6(TP53):c.646G>A (p.Val216Met)]

NM_000546.6(TP53):c.646G>A (p.Val216Met)

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.646G>A (p.Val216Met)

Other names:

p.V216M:GTG>ATG

HGVS:

NC_000017.11:g.7674885C>T
NG_017013.2:g.17666G>A
NM_000546.6:c.646G>AMANE SELECT
NM_001126112.3:c.646G>A
NM_001126113.3:c.646G>A
NM_001126114.3:c.646G>A
NM_001126115.2:c.250G>A
NM_001126116.2:c.250G>A
NM_001126117.2:c.250G>A
NM_001126118.2:c.529G>A
NM_001276695.3:c.529G>A
NM_001276696.3:c.529G>A
NM_001276697.3:c.169G>A
NM_001276698.3:c.169G>A
NM_001276699.3:c.169G>A
NM_001276760.3:c.529G>A
NM_001276761.3:c.529G>A
NP_000537.3:p.Val216Met
NP_000537.3:p.Val216Met
NP_001119584.1:p.Val216Met
NP_001119585.1:p.Val216Met
NP_001119586.1:p.Val216Met
NP_001119587.1:p.Val84Met
NP_001119588.1:p.Val84Met
NP_001119589.1:p.Val84Met
NP_001119590.1:p.Val177Met
NP_001263624.1:p.Val177Met
NP_001263625.1:p.Val177Met
NP_001263626.1:p.Val57Met
NP_001263627.1:p.Val57Met
NP_001263628.1:p.Val57Met
NP_001263689.1:p.Val177Met
NP_001263690.1:p.Val177Met
LRG_321t1:c.646G>A
LRG_321:g.17666G>A
LRG_321p1:p.Val216Met
NC_000017.10:g.7578203C>T
NM_000546.4:c.646G>A
NM_000546.5:c.646G>A
P04637:p.Val216Met

Protein change:

V177M

Links:

UniProtKB: P04637#VAR_005956; dbSNP: rs730882025

NCBI 1000 Genomes Browser:

rs730882025

Molecular consequence:

NM_000546.6:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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ARFGAP1 ADP ribosylation factor GTPase activating protein 1 [Homo sapiens]
ARFGAP1 ADP ribosylation factor GTPase activating protein 1 [Homo sapiens]
Gene ID:55738

Gene
Thymus numidicus (0)
Nucleotide
Uncultured bacterium clone OTU_8530 16S ribosomal RNA gene, partial sequence
Uncultured bacterium clone OTU_8530 16S ribosomal RNA gene, partial sequence
gi|1496546168|gb|MH532178.1|

Nucleotide
Uncultured bacterium clone OTU_8574 16S ribosomal RNA gene, partial sequence
Uncultured bacterium clone OTU_8574 16S ribosomal RNA gene, partial sequence
gi|1496546212|gb|MH532222.1|

Nucleotide
Uncultured bacterium clone OTU_8510 16S ribosomal RNA gene, partial sequence
Uncultured bacterium clone OTU_8510 16S ribosomal RNA gene, partial sequence
gi|1496546148|gb|MH532158.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211801	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 13, 2018)	germline	clinical testing	Citation Link,
SCV002067403	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 25, 2019)	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

SCV000211801

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 13, 2018)

germline

clinical testing

Citation Link,

SCV002067403

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 25, 2019)

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	yes	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 GeneDx, SCV000211801.10

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

Description

This variant is denoted TP53 c.646G>A at the cDNA level, p.Val216Met (V216M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). TP53 Val216Met has been reported in an individual with multiple sarcomas, another with adrenocortical carcinoma, as well as an unaffected male from a family meeting Chompret criteria for Li-Fraumeni syndrome (Cast?ra 2014, Bougeard 2015, Zerdoumi 2017). Multiple functional assays have found this variant to severely impact transcriptional activation and expression of typical p53 targets (Grochova 2008, Malcikova 2009, Slovackova 2010, Pekova 2011). Consistent with these results, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Val216Met was not observed in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider TP53 Val216Met to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002067403.1

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

Description

DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.646G>A, in exon 6 that results in an amino acid change, p.Val216Met. The p.Val216Met change has not been described in population databases (gnomAD, ExAC). This sequence change has been identified in a child with adrenocortical carcinoma (PMID: 26014290). Functional studies revealed that the p.Val216Met change results in a drastic change of p53 transcriptional activity, similar to that of dominant-negative mutations (PMID: 28369373). The p.Val216Met change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val216Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL)." DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.646G>A, in exon 6 that results in an amino acid change, p.Val216Met. The p.Val216Met change has not been described in population databases (gnomAD, ExAC). This sequence change has been identified in a child with adrenocortical carcinoma (PMID: 26014290). Functional studies revealed that the p.Val216Met change results in a drastic change of TP53 transcriptional activity, similar to that of dominant-negative mutations (PMID: 28369373). The p.Val216Met change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val216Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 11, 2024

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