NM_004304.5(ALK):c.1550A>G (p.His517Arg) AND Neuroblastoma 3

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Aug 14, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000529454.7

Allele description [Variation Report for NM_004304.5(ALK):c.1550A>G (p.His517Arg)]

NM_004304.5(ALK):c.1550A>G (p.His517Arg)

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.1550A>G (p.His517Arg)
HGVS:
  • NC_000002.12:g.29318401T>C
  • NG_009445.1:g.608166A>G
  • NM_004304.5:c.1550A>GMANE SELECT
  • NP_004295.2:p.His517Arg
  • LRG_488:g.608166A>G
  • NC_000002.11:g.29541267T>C
  • NM_004304.4:c.1550A>G
Protein change:
H517R
Links:
dbSNP: rs367674546
NCBI 1000 Genomes Browser:
rs367674546
Molecular consequence:
  • NM_004304.5:c.1550A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neuroblastoma 3 (NBLST3)
Synonyms:
NEUROBLASTOMA, SUSCEPTIBILITY TO, 3; ALK-Related Neuroblastoma Susceptibility
Identifiers:
MONDO: MONDO:0013083; MedGen: C2751681; Orphanet: 635; OMIM: 613014

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000429958Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000648618Invitaecriteria provided, single submitter
Uncertain significance
(Aug 14, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000429958.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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

From Invitae, SCV000648618.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces histidine with arginine at codon 517 of the ALK protein (p.His517Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs367674546, ExAC 0.03%). This variant has not been reported in the literature in individuals with ALK-related disease. ClinVar contains an entry for this variant (Variation ID: 335707). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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