ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3600G>C (p.Ala1200=) (rs56247462)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226022 SCV000288350 benign Neuroblastoma 3 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000226022 SCV000429930 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.
Ambry Genetics RCV000568764 SCV000672461 benign Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780826 SCV000918416 benign not specified 2018-07-03 criteria provided, single submitter clinical testing Variant summary: ALK c.3600G>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0039 in 276458 control chromosomes in the gnomAD database, including 31 homozygotes. The observed variant frequency is approximately 9306-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in ALK causing Neuroblastoma, Susceptibility Type 3 phenotype (4.2e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3600G>C in individuals affected with Neuroblastoma, Susceptibility Type 3 and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.

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