NM_000551.4(VHL):c.416C>G (p.Ser139Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001021981.7

Allele description [Variation Report for NM_000551.4(VHL):c.416C>G (p.Ser139Cys)]

NM_000551.4(VHL):c.416C>G (p.Ser139Cys)

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.416C>G (p.Ser139Cys)

Other names:

p.S139C:TCT>TGT

HGVS:

NC_000003.12:g.10146589C>G
NG_008212.3:g.9955C>G
NG_046756.1:g.4351C>G
NM_000551.4:c.416C>GMANE SELECT
NM_001354723.2:c.*18-3198C>G
NM_198156.3:c.341-3198C>G
NP_000542.1:p.Ser139Cys
NP_000542.1:p.Ser139Cys
LRG_322t1:c.416C>G
LRG_322:g.9955C>G
LRG_322p1:p.Ser139Cys
NC_000003.11:g.10188273C>G
NM_000551.3:c.416C>G
NM_198156.2:c.341-3198C>G

Protein change:

S139C

Links:

dbSNP: rs587780732

NCBI 1000 Genomes Browser:

rs587780732

Molecular consequence:

NM_001354723.2:c.*18-3198C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3198C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.416C>G - 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
SCV001183666	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25078357, 33938902 Citation Link,
SCV002534173	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 10, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001183666

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 30, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002534173

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 10, 2022)

germline

curation

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, curation

Citations

PubMed

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Hwang S, Ku CR, Lee JI, Hur KY, Lee MS, Lee CH, Koo KY, Lee JS, Rhee Y.

J Hum Genet. 2014 Sep;59(9):488-93. doi: 10.1038/jhg.2014.61. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25078357

Familial erythrocytosis 2 and von Hippel-Lindau disease in the same pediatric patient.

Núñez-Martínez PM, Taja-Chayeb L, Ramírez-Otero MA, Fragoso-Ontiveros V, Wegman-Ostrosky T, Cruz-Robles D, Vidal Millán S.

Bol Med Hosp Infant Mex. 2021 May 3;78(4):341-345. doi: 10.24875/BMHIM.20000129.

PubMed [citation]

PMID:: 33938902

Details of each submission

From Ambry Genetics, SCV001183666.4

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

Description

The p.S139C variant (also known as c.416C>G), located in coding exon 2 of the VHL gene, results from a C to G substitution at nucleotide position 416. The serine at codon 139 is replaced by cysteine, an amino acid with dissimilar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a VHL-causing variant based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). However, this variant was identified in conjunction with a pathogenic VHL deletion in a child with features suggestive of Chuvash polycythemia (Núñez-Martínez PM et al. Bol Med Hosp Infant Mex, 2021 May). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	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

From Sema4, Sema4, SCV002534173.1

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

#	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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