ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.2039C>T (p.Thr680Ile) (rs35228363)

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Total submissions: 10
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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,PreventionGenetics RCV000119966 SCV000310070 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000463467 SCV000429955 benign Neuroblastoma 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.
Invitae RCV000463467 SCV000554749 benign Neuroblastoma 3 2020-12-01 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: 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 3 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000463467 SCV000745626 benign Neuroblastoma 3 2016-01-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000463467 SCV001157115 benign Neuroblastoma 3 2020-06-19 criteria provided, single submitter clinical testing
ITMI RCV000119966 SCV000084096 not provided not specified 2013-09-19 no assertion provided reference population

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