Submissions for variant NM_004304.5(ALK):c.3452C>T (p.Thr1151Met)

gnomAD frequency: 0.00004  dbSNP: rs113994091

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001020341	SCV001181806	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-03	criteria provided, single submitter	clinical testing	The p.T1151M variant (also known as c.3452C>T), located in coding exon 22 of the ALK gene, results from a C to T substitution at nucleotide position 3452. The threonine at codon 1151 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the germline of an individual with neuroblastoma (George RE et al. Nature. 2008 Oct;455:975-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000019712	SCV001299378	likely benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019712	SCV001542216	uncertain significance	Neuroblastoma, susceptibility to, 3	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1151 of the ALK protein (p.Thr1151Met). This variant is present in population databases (rs113994091, gnomAD 0.01%). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18923525; internal data). ClinVar contains an entry for this variant (Variation ID: 18086). 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. Experimental studies have shown that this missense change does not substantially affect ALK function (PMID: 18923525, 23104988). 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.
GeneDx	RCV004589517	SCV005080614	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: ERK activation, foci stimulation, and auto-phosphorylation similar to wildtype (George et al., 2008; Chand et al., 2013); Identified in an individual with neuroblastoma and another with pediatric leukemia (George et al., 2008; Waanders et al., 2017); This variant is associated with the following publications: (PMID: 18923525, 22072639, 21838707, 27733777, 27009859, 23104988)
OMIM	RCV000019712	SCV000040010	risk factor	Neuroblastoma, susceptibility to, 3	2008-10-16	no assertion criteria provided	literature only
GeneReviews	RCV000019712	SCV000041066	not provided	Neuroblastoma, susceptibility to, 3		no assertion provided	literature only