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NM_000551.4(VHL):c.464-2A>G AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 30, 2023
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:
RCV000216737.6

Allele description [Variation Report for NM_000551.4(VHL):c.464-2A>G]

NM_000551.4(VHL):c.464-2A>G

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:
single nucleotide variant
Cytogenetic location:
3p25.3
Genomic location:
Preferred name:
NM_000551.4(VHL):c.464-2A>G
HGVS:
  • NC_000003.12:g.10149785A>G
  • NG_008212.3:g.13151A>G
  • NG_046756.1:g.7547A>G
  • NM_000551.4:c.464-2A>GMANE SELECT
  • NM_001354723.2:c.*18-2A>G
  • NM_198156.3:c.341-2A>G
  • LRG_322t1:c.464-2A>G
  • LRG_322:g.13151A>G
  • NC_000003.11:g.10191469A>G
  • NM_000551.3:c.464-2A>G
Links:
dbSNP: rs5030816
NCBI 1000 Genomes Browser:
rs5030816
Molecular consequence:
  • NM_000551.4:c.464-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354723.2:c.*18-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_198156.3:c.341-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
Functional consequence:
sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071] - Comment(s)

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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000273653Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jan 30, 2023) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV000273653.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.464-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 3 in the VHL gene. This mutation has been detected in a family meeting VHL clinical criteria (Glavac D et al. Hum Genet. 1996 Sep;98(3):271-80). In addition, two other alterations at this nucleotide position (c.464-2A>C and c.464-2A>T) have also been reported in VHL families and are considered pathogenic (Whaley JM et al. Am J Hum Genet. 1994 Dec;55(6):1092-102, Glavac D et al. Hum Genet. 1996 Sep;98(3):271-80). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic.

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

Last Updated: Nov 3, 2024