Submissions for variant NM_004304.5(ALK):c.2039C>T (p.Thr680Ile)

gnomAD frequency: 0.01598  dbSNP: rs35228363

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000119966	SCV000279444	benign	not specified	2016-09-20	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.
PreventionGenetics, part of Exact Sciences	RCV000119966	SCV000310070	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000463467	SCV000429955	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463467	SCV000554749	benign	Neuroblastoma, susceptibility to, 3	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567568	SCV000664958	benign	Hereditary cancer-predisposing syndrome	2016-12-14	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	RCV000589416	SCV000698287	likely benign	not provided	2016-08-24	criteria provided, single submitter	clinical testing	Variant summary: The ALK c.2039C>T (p.Thr680Ile) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1947/122770 control chromosomes (22 homozygotes) at a frequency of 0.0158589, which is approximately 38061 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004) based on the disease prevalence of neuroblastoma (susceptibility phenotype), suggesting this variant is likely a benign polymorphism. This variant has been reported in patients with breast cancer and prostate cancer as a germline variant and in patients with hemangioblastoma as a somatic variant; however without strong evidence for pathogenicity (Haiman_2013, Harismendy _2013, Shankar_2014). In a large case-control study that included patients with prostate cancer from multiple ethnicities (African American, Native Hawaiian, Japanese American, Latino and European American), it did not confer an increased risk for prostate cancer in the overall population (Haiman_2013). However, in African American subpopulation, it conferred an elevated risk (odd ratio: 3.104; p-value 0.00025), suggesting that it may confer an ethnicity-specific risk. More reproducible case-control studies are required to confirm this risk association. In ClinVar, one clinical lab has classified it as uncertain significance. Taken together, this variant is currently classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000463467	SCV000744256	likely benign	Neuroblastoma, susceptibility to, 3	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000463467	SCV001157115	benign	Neuroblastoma, susceptibility to, 3	2023-11-07	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000463467	SCV004016800	benign	Neuroblastoma, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000589416	SCV005263300	likely benign	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV000589416	SCV005433111	benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ALK: BS1, BS2
ITMI	RCV000119966	SCV000084096	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000463467	SCV000745626	benign	Neuroblastoma, susceptibility to, 3	2016-01-22	no assertion criteria provided	clinical testing