Submissions for variant NM_004304.5(ALK):c.3824G>A (p.Arg1275Gln)

dbSNP: rs113994087

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268655	SCV001447738	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000019709	SCV001478107	pathogenic	Neuroblastoma, susceptibility to, 3	2020-12-15	criteria provided, single submitter	research
Invitae	RCV000019709	SCV002224310	pathogenic	Neuroblastoma, susceptibility to, 3	2023-04-19	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV002354167	SCV002619803	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-29	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000019709	SCV000040007	risk factor	Neuroblastoma, susceptibility to, 3	2012-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000019709	SCV000041068	not provided	Neuroblastoma, susceptibility to, 3		no assertion provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000019709	SCV000256824	pathogenic	Neuroblastoma, susceptibility to, 3	2015-10-07	no assertion criteria provided	clinical testing
Database of Curated Mutations (DoCM)	RCV000432041	SCV000503769	pathogenic	Neuroblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440978	SCV000503770	likely pathogenic	Neoplasm of brain	2014-12-26	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423720	SCV000503771	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only