Submissions for variant NM_000051.4(ATM):c.3092A>T (p.Glu1031Val)

dbSNP: rs758708495

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537780	SCV000622389	uncertain significance	Ataxia-telangiectasia syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1031 of the ATM protein (p.Glu1031Val). ClinVar contains an entry for this variant (Variation ID: 453448). 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV000580540	SCV000682100	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1031 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 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.
Ambry Genetics	RCV000580540	SCV002606422	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-09-02	criteria provided, single submitter	clinical testing	The c.3092A>T variant (also known as p.E1031V), located in coding exon 20 of the ATM gene, results from an A to T substitution at nucleotide position 3092. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.