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NM_000546.6(TP53):c.646G>T (p.Val216Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 29, 2022
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:
RCV002365461.5

Allele description [Variation Report for NM_000546.6(TP53):c.646G>T (p.Val216Leu)]

NM_000546.6(TP53):c.646G>T (p.Val216Leu)

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>T (p.Val216Leu)
HGVS:
  • NC_000017.11:g.7674885C>A
  • NG_017013.2:g.17666G>T
  • NM_000546.6:c.646G>TMANE SELECT
  • NM_001126112.3:c.646G>T
  • NM_001126113.3:c.646G>T
  • NM_001126114.3:c.646G>T
  • NM_001126115.2:c.250G>T
  • NM_001126116.2:c.250G>T
  • NM_001126117.2:c.250G>T
  • NM_001126118.2:c.529G>T
  • NM_001276695.3:c.529G>T
  • NM_001276696.3:c.529G>T
  • NM_001276697.3:c.169G>T
  • NM_001276698.3:c.169G>T
  • NM_001276699.3:c.169G>T
  • NM_001276760.3:c.529G>T
  • NM_001276761.3:c.529G>T
  • NP_000537.3:p.Val216Leu
  • NP_000537.3:p.Val216Leu
  • NP_001119584.1:p.Val216Leu
  • NP_001119585.1:p.Val216Leu
  • NP_001119586.1:p.Val216Leu
  • NP_001119587.1:p.Val84Leu
  • NP_001119588.1:p.Val84Leu
  • NP_001119589.1:p.Val84Leu
  • NP_001119590.1:p.Val177Leu
  • NP_001263624.1:p.Val177Leu
  • NP_001263625.1:p.Val177Leu
  • NP_001263626.1:p.Val57Leu
  • NP_001263627.1:p.Val57Leu
  • NP_001263628.1:p.Val57Leu
  • NP_001263689.1:p.Val177Leu
  • NP_001263690.1:p.Val177Leu
  • LRG_321t1:c.646G>T
  • LRG_321:g.17666G>T
  • LRG_321p1:p.Val216Leu
  • NC_000017.10:g.7578203C>A
  • NM_000546.4:c.646G>T
  • NM_000546.5:c.646G>T
Protein change:
V177L
Links:
dbSNP: rs730882025
NCBI 1000 Genomes Browser:
rs730882025
Molecular consequence:
  • NM_000546.6:c.646G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.646G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.646G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.646G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.250G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.250G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.250G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.529G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.529G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.529G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.169G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.169G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.169G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.529G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.529G>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002656919Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Mar 29, 2022) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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, SCV002656919.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The p.V216L pathogenic mutation (also known as c.646G>T), located in coding exon 5 of the TP53 gene, results from a G to T substitution at nucleotide position 646. The valine at codon 216 is replaced by leucine, an amino acid with highly similar properties. 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). 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). Another alteration at the same codon, p.V216M (c.646G>A), has been detected in a child diagnosed with adrenocorticol carcinoma and in an individual with a personal history of alveolar rhabdomyosarcoma and soft tissue sarcoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2812). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024