Submissions for variant NM_000051.4(ATM):c.2500_2501delinsCT (p.Glu834Leu)

dbSNP: rs879254208

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235846	SCV000293837	uncertain significance	not provided	2016-01-18	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2500_2501delGAinsCT at the cDNA level, p.Glu834Leu (E834L) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is TGGA[GA][CT]AGTA. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Glutamic Acid to a Leucine (GAA>CTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither ATM c.2500_2501delGAinsCT nor ATM Glu834Leu (by this or an alternate nucleotide change) was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Glu834Leu occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). Based on currently available evidence, it is unclear whether ATM Glu834Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857815	SCV002172475	uncertain significance	Ataxia-telangiectasia syndrome	2022-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with leucine, which is neutral and non-polar, at codon 834 of the ATM protein (p.Glu834Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 246328). This variant has not been reported in the literature in individuals affected with ATM-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database.
Ambry Genetics	RCV002429156	SCV002741904	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-08	criteria provided, single submitter	clinical testing	The c.2500_2501delGAinsCT variant, located in coding exon 16 of the ATM gene, results from an in-frame deletion of GA and insertion of CT at nucleotide positions 2500 to 2501. This results in the substitution of the glutamic acid residue for a leucine residue at codon 834, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.