Submissions for variant NM_000051.4(ATM):c.4640T>C (p.Ile1547Thr)

gnomAD frequency: 0.00001  dbSNP: rs1555100432

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565964	SCV000672632	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-09	criteria provided, single submitter	clinical testing	The p.I1547T variant (also known as c.4640T>C), located in coding exon 30 of the ATM gene, results from a T to C substitution at nucleotide position 4640. The isoleucine at codon 1547 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054415	SCV001218728	uncertain significance	Ataxia-telangiectasia syndrome	2024-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1547 of the ATM protein (p.Ile1547Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 485175). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493664	SCV004243445	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001528548	SCV005623922	uncertain significance	not provided	2024-08-22	criteria provided, single submitter	clinical testing	The ATM c.4640T>C (p.Ile1547Thr) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 28779002 (2017), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/ATM), 35884425 (2022)) as well as reportedly healthy individuals (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/ATM), 35884425 (2022)). The frequency of this variant in the general population, 0.0000041 (1/244654 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528548	SCV001740439	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001528548	SCV001905799	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001528548	SCV002036939	uncertain significance	not provided		no assertion criteria provided	clinical testing