NM_004304.5(ALK):c.3509T>A (p.Ile1170Asn) AND Neuroblastoma, susceptibility to, 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 17, 2017
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:: RCV000533103.6

Allele description [Variation Report for NM_004304.5(ALK):c.3509T>A (p.Ile1170Asn)]

NM_004304.5(ALK):c.3509T>A (p.Ile1170Asn)

Gene:

ALK:ALK receptor tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.2

Genomic location:

Preferred name:

NM_004304.5(ALK):c.3509T>A (p.Ile1170Asn)

HGVS:

NC_000002.12:g.29222350A>T
NG_009445.1:g.704217T>A
NM_001353765.2:c.305T>A
NM_004304.5:c.3509T>AMANE SELECT
NP_001340694.1:p.Ile102Asn
NP_004295.2:p.Ile1170Asn
LRG_488:g.704217T>A
NC_000002.11:g.29445216A>T
NM_004304.4:c.3509T>A

Protein change:

I102N

Links:

dbSNP: rs1553394197

NCBI 1000 Genomes Browser:

rs1553394197

Molecular consequence:

NM_001353765.2:c.305T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004304.5:c.3509T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuroblastoma, susceptibility to, 3
Synonyms:: Neuroblastoma 3; ALK-Related Neuroblastoma Susceptibility
Identifiers:: MONDO: MONDO:0013083; MedGen: C2751681; Orphanet: 635; OMIM: 613014

Recent activity

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Mus musculus leucyl/cystinyl aminopeptidase, mRNA (cDNA clone MGC:144172 IMAGE:4...
Mus musculus leucyl/cystinyl aminopeptidase, mRNA (cDNA clone MGC:144172 IMAGE:40098428), complete cds
gi|111305421|gb|BC120926.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000648698	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 17, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18724359, 21972109, 18923524, 25517749, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000648698

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 17, 2017)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Identification of ALK as a major familial neuroblastoma predisposition gene.

Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM.

Nature. 2008 Oct 16;455(7215):930-5. doi: 10.1038/nature07261. Epub 2008 Aug 24.

PubMed [citation]

PMID:: 18724359
PMCID:: PMC2672043

Germline gain-of-function mutations of ALK disrupt central nervous system development.

de Pontual L, Kettaneh D, Gordon CT, Oufadem M, Boddaert N, Lees M, Balu L, Lachassinne E, Petros A, Mollet J, Wilson LC, Munnich A, Brugière L, Delattre O, Vekemans M, Etchevers H, Lyonnet S, Janoueix-Lerosey I, Amiel J.

Hum Mutat. 2011 Mar;32(3):272-6. doi: 10.1002/humu.21442.

PubMed [citation]

PMID:: 21972109

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000648698.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

In summary, this variant has been shown to disrupt protein function in vitro. However, further genetic data is necessary at this point to unequivocally classify this variant. Therefore, it has been classified as a Variant of Uncertain Significance. This missense change is located within the functionally conserved tyrosine kinase domain of the ALK protein, where a significant number of previously reported somatic and germline ALK missense mutations have been reported (PMID: 18724359, 21972109, 18923524). One experimental study has shown that this variant accelerated the autophosphorylation of the ALK tyrosine kinase domain in vitro, which is necessary for its activation (PMID: 25517749). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 1170 of the ALK protein (p.Ile1170Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This has not been reported in the literature in the germline of individuals with an ALK-related disease.

#	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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