ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.1215A>T (p.Glu405Asp)

gnomAD frequency: 0.00001  dbSNP: rs370235133
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000471259 SCV000554730 likely benign Neuroblastoma, susceptibility to, 3 2024-01-24 criteria provided, single submitter clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000471259 SCV004017044 likely benign Neuroblastoma, susceptibility to, 3 2023-07-07 criteria provided, single submitter clinical testing
ITMI RCV000119988 SCV000084118 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357328 SCV001552770 likely benign not provided no assertion criteria provided clinical testing The ALK p.E405D variant was not identified in the literature nor was it identified in COSMIC. The variant was identified in dbSNP (ID: rs370235133) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 97 of 282670 chromosomes (2 homozygous) at a frequency of 0.0003432, and was observed at the highest frequency in the South Asian population in 94 of 30614 chromosomes (2 homozygous) (freq: 0.003070) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E405 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. 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.

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