Submissions for variant NM_000051.4(ATM):c.743G>A (p.Arg248Gln)

dbSNP: rs769166447

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567418	SCV000660656	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.R248Q variant (also known as c.743G>A), located in coding exon 6 of the ATM gene, results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with highly similar properties. A different alteration at this position, c.743G>T, was reported in an individual with a mild ataxia phenotype, and was demonstrated to result in some expression of ATM protein and retained ATM kinase activity (Cummins G et al. Parkinsonism Relat. Disord., 2013 Dec;19:1173-4). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000567418	SCV000682414	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805334	SCV000945286	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the ATM protein (p.Arg248Gln). This variant is present in population databases (rs769166447, gnomAD 0.003%). 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: 479015). 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.
Athena Diagnostics	RCV001662611	SCV001879567	uncertain significance	not provided	2020-11-10	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289775	SCV002579646	uncertain significance	Familial cancer of breast	2021-11-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002289775	SCV004209402	uncertain significance	Familial cancer of breast	2023-11-29	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002289775	SCV005329583	uncertain significance	Familial cancer of breast	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.743G>A (p.Arg248Gln) in the ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance by multiple submitters. However, no details are available for independent assessment. The amino acid Arginine at position 248 is changed to a Glutamine changing protein sequence and it might alter its composition and physico- chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Natera, Inc.	RCV000805334	SCV001454846	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing