Submissions for variant NM_000051.4(ATM):c.3025G>C (p.Glu1009Gln)

dbSNP: rs1064794039

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478303	SCV000567648	uncertain significance	not provided	2016-10-13	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3025G>C at the cDNA level, p.Glu1009Gln (E1009Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Glu1009Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Glu1009Gln occurs at a position that is conserved across species and is located within the beta-adaptin interaction domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Glu1009Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627870	SCV000748754	uncertain significance	Ataxia-telangiectasia syndrome	2021-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1009 of the ATM protein (p.Glu1009Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. ClinVar contains an entry for this variant (Variation ID: 419680). This variant has not been reported in the literature in individuals affected with ATM-related conditions.
Ambry Genetics	RCV002436533	SCV002753104	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.E1009Q variant (also known as c.3025G>C), located in coding exon 19 of the ATM gene, results from a G to C substitution at nucleotide position 3025. The glutamic acid at codon 1009 is replaced by glutamine, an amino acid with highly similar properties. This alteration was not observed in 7051 unselected female breast cancer patients, 11241 female controls of Japanese ancestry, or in 53 unselected male breast cancer patients; however, it was reported with a carrier frequency of 0.00008 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
Baylor Genetics	RCV003470545	SCV004210202	uncertain significance	Familial cancer of breast	2023-07-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701530	SCV005203758	uncertain significance	not specified	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3025G>C (p.Glu1009Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276254 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3025G>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 419680). Based on the evidence outlined above, the variant was classified as uncertain significance.