Submissions for variant NM_000051.4(ATM):c.7332G>C (p.Glu2444Asp)

dbSNP: rs876658886

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217221	SCV000274704	uncertain significance	Hereditary cancer-predisposing syndrome	2018-05-30	criteria provided, single submitter	clinical testing	The p.E2444D variant (also known as c.7332G>C), located in coding exon 49 of the ATM gene, results from a G to C substitution at nucleotide position 7332. The glutamic acid at codon 2444 is replaced by aspartic acid, an amino acid with highly similar properties. 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 p.E2444D remains unclear.
GeneDx	RCV000479125	SCV000567811	uncertain significance	not provided	2015-08-27	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.7332G>C at the cDNA level, p.Glu2444Asp (E2444D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Glu2444Asp 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 Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. ATM Glu2444Asp occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013, UniProt). 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 Glu2444Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000217221	SCV000904775	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 2444 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001232691	SCV001405258	uncertain significance	Ataxia-telangiectasia syndrome	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2444 of the ATM protein (p.Glu2444Asp). 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: 230986). 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.