Submissions for variant NM_000051.4(ATM):c.7370A>C (p.Glu2457Ala)

dbSNP: rs778482902

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218733	SCV000275191	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	The p.E2457A variant (also known as c.7370A>C), located in coding exon 49 of the ATM gene, results from an A to C substitution at nucleotide position 7370. The glutamic acid at codon 2457 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000485580	SCV000571025	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in a patient with breast cancer (PMID: 36200007); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35585550, 23532176, 36200007)
Color Diagnostics, LLC DBA Color Health	RCV000218733	SCV000687768	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 2457 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 36200007). This variant has been identified in 11/251274 chromosomes 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	RCV000701716	SCV000830529	likely benign	Ataxia-telangiectasia syndrome	2023-12-30	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338466	SCV004046959	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant p.E2457A in ATM (NM_000051.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.E2457A variant has a GnomAD frequency of 0.00004378 % and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glutamic acid and alanine. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu2457Ala in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000485580	SCV005412474	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	BP4
Natera, Inc.	RCV000701716	SCV002080588	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-09	no assertion criteria provided	clinical testing