Submissions for variant NM_004304.5(ALK):c.4338C>T (p.Thr1446=)

gnomAD frequency: 0.10831  dbSNP: rs56132472

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000244172	SCV000310076	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000390900	SCV000429921	benign	Neuroblastoma, susceptibility to, 3	2018-01-13	criteria provided, single submitter	clinical testing	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000244172	SCV000518972	benign	not specified	2016-06-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000569897	SCV000664944	benign	Hereditary cancer-predisposing syndrome	2016-12-12	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	RCV000588694	SCV000698295	benign	not provided	2016-04-26	criteria provided, single submitter	clinical testing	Variant summary: The c.4338C>T variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts benign outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts changes of binding motifs for splicing enhancers. This variant is found in 10961/117122 control chromosomes (649 homozygotes) at a frequency of 0.0935862, which is about 224607 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting this variant is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000390900	SCV001733358	benign	Neuroblastoma, susceptibility to, 3	2025-02-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000390900	SCV004016519	benign	Neuroblastoma, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000588694	SCV005238713	benign	not provided		criteria provided, single submitter	not provided
Faculté Pluridciplinaire Nador, Université Mohamed Premier	RCV001250940	SCV001250923	likely benign	Squamous cell lung carcinoma	2020-05-05	no assertion criteria provided	clinical testing