Submissions for variant NM_004304.5(ALK):c.469C>T (p.Pro157Ser)

gnomAD frequency: 0.00055  dbSNP: rs74774946

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229990	SCV000288368	likely benign	Neuroblastoma, susceptibility to, 3	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022915	SCV001184711	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-30	criteria provided, single submitter	clinical testing	The p.P157S variant (also known as c.469C>T), located in coding exon 1 of the ALK gene, results from a C to T substitution at nucleotide position 469. The proline at codon 157 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000229990	SCV001302492	uncertain significance	Neuroblastoma, susceptibility to, 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001824304	SCV002009878	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001824304	SCV002074023	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV001022915	SCV002528517	likely benign	Hereditary cancer-predisposing syndrome	2020-11-05	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000229990	SCV004563173	uncertain significance	Neuroblastoma, susceptibility to, 3	2023-10-05	criteria provided, single submitter	clinical testing	The ALK c.469C>T; p.Pro157Ser variant (rs74774946), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 239842). This variant is found in the non-Finnish European population with an allele frequency of 0.063% (79/125,556 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.031). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time.
PreventionGenetics, part of Exact Sciences	RCV004745302	SCV005357603	uncertain significance	ALK-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The ALK c.469C>T variant is predicted to result in the amino acid substitution p.Pro157Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239842). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.