Submissions for variant NM_004304.5(ALK):c.4796C>A (p.Pro1599His)

gnomAD frequency: 0.00091  dbSNP: rs1881423

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472979	SCV000554782	likely benign	Neuroblastoma, susceptibility to, 3	2024-01-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000472979	SCV001482609	uncertain significance	Neuroblastoma, susceptibility to, 3	2019-07-31	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001356607	SCV001785917	uncertain significance	not provided	2022-05-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with advanced cancer, type not specified (Mandelker 2017); This variant is associated with the following publications: (PMID: 24728327, 31888289, 28873162)
Sema4, Sema4	RCV002257415	SCV002528524	likely benign	Hereditary cancer-predisposing syndrome	2021-10-24	criteria provided, single submitter	curation
ITMI	RCV000119981	SCV000084111	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356607	SCV001551823	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ALK p.Pro1599His variant was identified in 2 of 9032 proband chromosomes (frequency: 0.00022) from individuals or families with cancer, and was present in 1 of 1598 control chromosomes (frequency: 0.00063) from healthy individuals (Bodian_2014_PMID:24728327; Mandelker_2017_PMID: 28873162; Yehia_2018_PMID: 29684080). The variant was also identified in dbSNP (ID: rs1881423) and ClinVar (classified as likely benign by Invitae in 2017). The variant was not identified in the COGR, Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in control databases in 75 of 282614 chromosomes at a frequency of 0.000265 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 64 of 24968 chromosomes (freq: 0.002563), Latino in 10 of 35436 chromosomes (freq: 0.000282) and Other in 1 of 7214 chromosomes (freq: 0.000139), it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The p.Pro1599 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003935135	SCV004757210	likely benign	ALK-related disorder	2019-03-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).