NM_000551.4(VHL):c.292T>C (p.Tyr98His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 17, 2024
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:: RCV000492094.12

Allele description [Variation Report for NM_000551.4(VHL):c.292T>C (p.Tyr98His)]

NM_000551.4(VHL):c.292T>C (p.Tyr98His)

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.292T>C (p.Tyr98His)

HGVS:

NC_000003.12:g.10142139T>C
NG_008212.3:g.5505T>C
NM_000551.4:c.292T>CMANE SELECT
NM_001354723.2:c.292T>C
NM_198156.3:c.292T>C
NP_000542.1:p.Tyr98His
NP_000542.1:p.Tyr98His
NP_001341652.1:p.Tyr98His
NP_937799.1:p.Tyr98His
LRG_322t1:c.292T>C
LRG_322:g.5505T>C
LRG_322p1:p.Tyr98His
NC_000003.11:g.10183823T>C
NM_000551.2:c.292T>C
NM_000551.3:c.292T>C
P40337:p.Tyr98His
p.[Tyr98His]

Protein change:

Y98H; TYR98HIS

Links:

UniProtKB: P40337#VAR_005707; OMIM: 608537.0009; dbSNP: rs5030809

NCBI 1000 Genomes Browser:

rs5030809

Molecular consequence:

NM_000551.4:c.292T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.292T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.292T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580959	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 17, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12000816, 12510195, 15300849, 19336503, 19602254, 20660572, 21204227, 23434161, 29625052, 30902965, 31538058, 7987306 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580959

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 17, 2024)

germline

clinical testing

PubMed (12)
[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

Germ-line mutations in nonsyndromic pheochromocytoma.

Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, et al.

N Engl J Med. 2002 May 9;346(19):1459-66.

PubMed [citation]

PMID:: 12000816

Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL.

Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W.

Nat Cell Biol. 2003 Jan;5(1):64-70.

PubMed [citation]

PMID:: 12510195

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000580959.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The p.Y98H pathogenic mutation (also known as c.292T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 292. The tyrosine at codon 98 is replaced by histidine, an amino acid with similar properties. This mutation has been reported in numerous VHL families in the literature (Crossey PA et al. Hum Mol Genet. 1994 Aug;3:1303-8; Neumann HP et al. N Engl J Med. 2002 May;346:1459-66; Gallou C et al. Hum. Mutat. 2004 Sep;24:215-24; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Erlic Z et al. Endocr Relat Cancer. 2010 Dec;17:875-83; Nielsen SM et al. Am J Med Genet A. 2011 Jan;155A:168-73; Klingler JH et al. J Stroke Cerebrovasc Dis. 2013 May;22:437-43; Huang KL et al. Cell. 2018 04;173:355-370.e14; Liu P et al. Gland Surg, 2019 Aug;8:343-353). In addition, this mutation was shown to disrupt microtubule stabilization in vitro and has been noted to be associated with Type 2A VHL (Hergovich A et al. Nat Cell Biol. 2003;5(1):64-70; Bangiyeva V et al. BMC Cancer. 2009;9:229). Of note, this may be referred to as c.505T>A in some literature. Based on available evidence to date, this alteration is considered 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: Oct 26, 2024

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