Submissions for variant NM_004304.5(ALK):c.4297GAG[2] (p.Glu1435del)

dbSNP: rs138827116

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230850	SCV000288360	benign	Neuroblastoma, susceptibility to, 3	2025-02-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000119975	SCV000333812	benign	not specified	2015-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000306508	SCV000429922	likely benign	Neuroblastoma Susceptibility	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022251	SCV001183966	benign	Hereditary cancer-predisposing syndrome	2018-09-24	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000119975	SCV003929356	likely benign	not specified	2023-04-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000230850	SCV005876354	likely benign	Neuroblastoma, susceptibility to, 3	2024-02-27	criteria provided, single submitter	clinical testing
ITMI	RCV000119975	SCV000084105	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356162	SCV001551251	likely benign	not provided		no assertion criteria provided	clinical testing	The ALK p.Glu1435del variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138827116) and in ClinVar (classified as likely benign by EGL Genetics and Illumina and as benign by Invitae). The variant was identified in control databases in 488 of 266110 chromosomes (4 homozygous) at a frequency of 0.001834 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 456 of 24732 chromosomes (freq: 0.01844), Other in 4 of 6686 chromosomes (freq: 0.000598), Latino in 18 of 33230 chromosomes (freq: 0.000542), Ashkenazi Jewish in 2 of 8558 chromosomes (freq: 0.000234), European (non-Finnish) in 7 of 122668 chromosomes (freq: 0.000057) and South Asian in 1 of 26748 chromosomes (freq: 0.000037); it was not observed in the East Asian and European (Finnish) populations. This variant is an in-frame deletion resulting in the removal of a glutamic acid (Glu) residue at codon 1435; the impact of this alteration on ALK protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.