NM_000551.4(VHL):c.263_265dup (p.Trp88_Leu89insArg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 1, 2018
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:: RCV000492430.4

Allele description [Variation Report for NM_000551.4(VHL):c.263_265dup (p.Trp88_Leu89insArg)]

NM_000551.4(VHL):c.263_265dup (p.Trp88_Leu89insArg)

Gene:

VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.263_265dup (p.Trp88_Leu89insArg)

HGVS:

NC_000003.12:g.10142110_10142112dup
NG_008212.3:g.5476_5478dup
NM_000551.4:c.263_265dupMANE SELECT
NM_001354723.2:c.263_265dup
NM_198156.3:c.263_265dup
NP_000542.1:p.Trp88_Leu89insArg
NP_001341652.1:p.Trp88_Leu89insArg
NP_937799.1:p.Trp88_Leu89insArg
LRG_322:g.5476_5478dup
NC_000003.11:g.10183794_10183796dup
NM_000551.3:c.263_265dupGGC

Links:

dbSNP: rs1131690960

NCBI 1000 Genomes Browser:

rs1131690960

Molecular consequence:

NM_000551.4:c.263_265dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001354723.2:c.263_265dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_198156.3:c.263_265dup - inframe_insertion - [Sequence Ontology: SO:0001821]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580983	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 1, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12004076, 23102223 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580983

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 1, 2018)

germline

clinical testing

PubMed (2)
[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

Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling.

Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP.

Science. 2002 Jun 7;296(5574):1886-9. Epub 2002 May 9.

PubMed [citation]

PMID:: 12004076

Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface.

Van Molle I, Thomann A, Buckley DL, So EC, Lang S, Crews CM, Ciulli A.

Chem Biol. 2012 Oct 26;19(10):1300-12. doi: 10.1016/j.chembiol.2012.08.015.

PubMed [citation]

PMID:: 23102223
PMCID:: PMC3551621

Details of each submission

From Ambry Genetics, SCV000580983.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.263_265dupGGC variant (also known as p.W88_L89insR), located in coding exon 1 of the VHL gene, results from an in-frame duplication of GGC at nucleotide positions 263 to 265, and results in the insertion of an extra arginine residue between codons 88 and 89. This alteration has been identified in unrelated individuals meeting diagnostic criteria for Von Hippel-Lindau (VHL) (Ambry internal data). Further, multiple similar non-truncating alterations in this region (p.W88R, p.W88L, p.W88C, p.L89P) have been reported in individuals satisfying established diagnostic criteria for VHL (Chen F, Hum. Mutat. 1995 ; 5(1):66-75, Kondo, et al. Hum. Mol. Genet. 1995 Dec; 4(12):2233-7, Gläsker S, J. Neurol. Neurosurg. Psychiatr. 1999 Dec; 67(6):758-62, Rocha JC, J. Med. Genet. 2003 Mar; 40(3):e31; Ong KR et al. Hum Mutat. 2007;28(2):143-149). In addition, based on internal structural assessment, this alteration results in local structural perturbation of the VHL protein fold, near the HIF1α-peptide-binding site (Min JH et al. Science, 2002 Jun;296:1886-9; Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). The duplicated nucleotide region is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be 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 1, 2024

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