ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.522C>A (p.Phe174Leu)

gnomAD frequency: 0.00001  dbSNP: rs587778020
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647378 SCV000769173 uncertain significance Neuroblastoma, susceptibility to, 3 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 174 of the ALK protein (p.Phe174Leu). This variant is present in population databases (rs587778020, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 133458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago RCV000119962 SCV002065770 uncertain significance not specified 2021-12-08 criteria provided, single submitter clinical testing DNA sequence analysis of the ALK gene demonstrated a sequence change, c.522C>A, in exon 1 that results in an amino acid change, p.Phe174Leu. This sequence change has been described in the gnomAD database with a frequency of 0.007% in the non-Finnish European subpopulation (dbSNP rs587778020). The p.Phe174Leu change affects a poorly conserved amino acid residue located in a domain of the ALK protein that is not known to be functional. The p.Phe174Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with ALK-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Phe174Leu change remains unknown at this time.
Sema4, Sema4 RCV002258794 SCV002528528 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-13 criteria provided, single submitter curation
GeneDx RCV003332121 SCV004040239 uncertain significance not provided 2023-03-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with a history of early-onset colorectal cancer, as well as in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014; Thutkawkorapin et al., 2019); This variant is associated with the following publications: (PMID: 30809968, 24728327, 31526103)
CeGaT Center for Human Genetics Tuebingen RCV003332121 SCV004144047 uncertain significance not provided 2022-07-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000647378 SCV004199951 uncertain significance Neuroblastoma, susceptibility to, 3 2023-08-05 criteria provided, single submitter clinical testing
ITMI RCV000119962 SCV000084092 not provided not specified 2013-09-19 no assertion provided reference population

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