Submissions for variant NM_000051.4(ATM):c.5674G>A (p.Glu1892Lys)

gnomAD frequency: 0.00002  dbSNP: rs730881375

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159736	SCV000209750	uncertain significance	not provided	2019-03-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694433	SCV000822879	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1892 of the ATM protein (p.Glu1892Lys). This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. This variant is present in population databases (rs730881375, gnomAD 0.01%). 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: 181969). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV000771875	SCV000904623	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the last nucleotide position of exon 37 of the ATM gene and replaces glutamic acid with lysine at codon 1892 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). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing, although this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/249836 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.
Ambry Genetics	RCV000771875	SCV001186400	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	The p.E1892K variant (also known as c.5674G>A), located in coding exon 36 of the ATM gene, results from a G to A substitution at nucleotide position 5674. The amino acid change results in glutamic acid to lysine at codon 1892, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 36, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this 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.
Sema4, Sema4	RCV000771875	SCV002529079	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	curation
Baylor Genetics	RCV003467234	SCV004210105	uncertain significance	Familial cancer of breast	2024-03-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000694433	SCV002084974	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-21	no assertion criteria provided	clinical testing