NM_000551.4(VHL):c.533_534del (p.Leu178fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 9, 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:: RCV002343616.2

Allele description [Variation Report for NM_000551.4(VHL):c.533_534del (p.Leu178fs)]

NM_000551.4(VHL):c.533_534del (p.Leu178fs)

Genes:

LOC107303340:3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region [Gene]
VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.533_534del (p.Leu178fs)

HGVS:

NC_000003.12:g.10149856_10149857del
NG_008212.3:g.13222_13223del
NG_046756.1:g.7618_7619del
NM_000551.4:c.533_534delMANE SELECT
NM_001354723.2:c.*87_*88del
NM_198156.3:c.410_411del
NP_000542.1:p.Leu178fs
NP_937799.1:p.Leu137fs
LRG_322:g.13222_13223del
NC_000003.11:g.10191540_10191541del
NM_000551.3:c.533_534delTG

Protein change:

L137fs

Links:

dbSNP: rs1559429736

NCBI 1000 Genomes Browser:

rs1559429736

Molecular consequence:

NM_001354723.2:c.*87_*88del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.533_534del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_198156.3:c.410_411del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002646837	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 9, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002646837

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 9, 2022)

germline

clinical testing

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

Details of each submission

From Ambry Genetics, SCV002646837.2

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

Description

The c.533_534delTG pathogenic mutation, located in coding exon 3 of the VHL gene, results from a deletion of two nucleotides at nucleotide positions 533 to 534, causing a translational frameshift with a predicted alternate stop codon (p.L178Rfs*77). This alteration occurs at the 3' terminus of theVHL gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 40 amino acids. This frameshift impacts the last 36amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with VHL-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Last Updated: Sep 29, 2024

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