NM_000268.4(NF2):c.599+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 24, 2021
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:: RCV002258342.4

Allele description [Variation Report for NM_000268.4(NF2):c.599+1G>A]

NM_000268.4(NF2):c.599+1G>A

Gene:

NF2:NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.2

Genomic location:

Preferred name:

NM_000268.4(NF2):c.599+1G>A

HGVS:

NC_000022.11:g.29655677G>A
NG_009057.1:g.57122G>A
NM_000268.4:c.599+1G>AMANE SELECT
NM_001407053.1:c.485+1G>A
NM_001407054.1:c.476+1G>A
NM_001407055.1:c.473+1G>A
NM_001407056.1:c.485+1G>A
NM_001407057.1:c.599+1G>A
NM_001407058.1:c.476+1G>A
NM_001407059.1:c.599+1G>A
NM_001407060.1:c.599+1G>A
NM_001407062.1:c.476+1G>A
NM_001407063.1:c.350+1G>A
NM_001407064.1:c.350+1G>A
NM_001407065.1:c.65+1G>A
NM_001407066.1:c.599+1G>A
NM_001407067.1:c.368+1G>A
NM_016418.5:c.599+1G>A
NM_181825.3:c.599+1G>A
NM_181828.3:c.473+1G>A
NM_181829.3:c.476+1G>A
NM_181830.3:c.350+1G>A
NM_181831.3:c.350+1G>A
NM_181832.3:c.599+1G>A
NM_181833.3:c.447+13392G>A
LRG_511t1:c.599+1G>A
LRG_511t2:c.599+1G>A
LRG_511:g.57122G>A
NC_000022.10:g.30051666G>A
NM_000268.3:c.599+1G>A

Links:

dbSNP: rs1555993352

NCBI 1000 Genomes Browser:

rs1555993352

Molecular consequence:

NM_181833.3:c.447+13392G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407053.1:c.485+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407054.1:c.476+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407055.1:c.473+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407056.1:c.485+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407057.1:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407058.1:c.476+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407059.1:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407060.1:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407062.1:c.476+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407063.1:c.350+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407064.1:c.350+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407065.1:c.65+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407066.1:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407067.1:c.368+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_016418.5:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181825.3:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181828.3:c.473+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181829.3:c.476+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181830.3:c.350+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181831.3:c.350+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181832.3:c.599+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV002528198	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Sep 24, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 7759081, 9643284, 16983642 Citation Link,
SCV002655724	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 2, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17222329, 7759081 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002528198

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Sep 24, 2021)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002655724

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 2, 2017)

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, curation

Citations

PubMed

Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.

Evans DG, Trueman L, Wallace A, Collins S, Strachan T.

J Med Genet. 1998 Jun;35(6):450-5. Erratum in: J Med Genet 1999 Jan;36(1):87.

PubMed [citation]

PMID:: 9643284
PMCID:: PMC1051337

Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings.

Ahronowitz I, Xin W, Kiely R, Sims K, MacCollin M, Nunes FP.

Hum Mutat. 2007 Jan;28(1):1-12.

PubMed [citation]

PMID:: 16983642

See all PubMed Citations (4)

Details of each submission

From Sema4, Sema4, SCV002528198.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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 Ambry Genetics, SCV002655724.2

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

Description

The c.599+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the NF2 gene. This alteration has been previously identified in the germline of one individual with neurofibromatosis 2 (NF2) and in the tumor of another individual with meningioma (Bourn D et al. Hum. Genet., 1995 May;95:572-4; Hansson CM et al. BMC Genomics, 2007 Jan;8:16). 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 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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