2-29209798-C-T

Position:

• chr2-29209798-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004304.5(ALK):​c.3824G>A​(p.Arg1275Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1275L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:2
• Conservation: PhyloP100: 7.90

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Protein kinase (size 276) in uniprot entity ALK_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_004304.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-29209798-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376365.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-29209798-C-T is Pathogenic according to our data. Variant chr2-29209798-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.3824G>A	p.Arg1275Gln	missense_variant	25/29	ENST00000389048.8
ALK	NM_001353765.2	c.620G>A	p.Arg207Gln	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.3824G>A	p.Arg1275Gln	missense_variant	25/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Pathogenic:3 Other:2

risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 07, 2015	- -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 19, 2023	Experimental studies have shown that this missense change affects ALK function (PMID: 18923523, 18923525). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 18083). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359, 18923523, 18923525, 29489754, 30350464; 18724359.). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1275 of the ALK protein (p.Arg1275Gln). -

Neuroblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2022

The p.R1275Q pathogenic mutation (also known as c.3824G>A), located in coding exon 25 of the ALK gene, results from a G to A substitution at nucleotide position 3824. The arginine at codon 1275 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in the germline of several unrelated families with neuroblastoma and confirmed de novo in at least one affected individual (Mossé YP et al. Nature, 2008 Oct;455:930-5, Janoueix-Lerosey I et al. Nature, 2008 Oct;455:967-70, Kudo K et al. Genes Chromosomes Cancer, 2018 12;57:665-669, Ambry internal data). In addition, this alteration has been shown to constitutively activate the ALK tyrosine kinase domain using a peptide phosphorylation assay (Bresler SC et al. Sci Transl Med, 2011 Nov;3:108ra114). Furthermore, this alteration was able to drive the transformation of NIH/3T3 cells in a transformation assay (Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.9	.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	.;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0030	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.99, 1.0
MutPred		0.96		.;Loss of MoRF binding (P = 0.0261);.;
MVP		0.98
MPC		0.76
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113994087; hg19: chr2-29432664; COSMIC: COSV66555567;