Submissions for variant NM_000051.4(ATM):c.3040G>A (p.Ala1014Thr)

gnomAD frequency: 0.00002  dbSNP: rs587782163

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130755	SCV000185646	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-17	criteria provided, single submitter	clinical testing	The p.A1014T variant (also known as c.3040G>A), located in coding exon 19 of the ATM gene, results from a G to A substitution at nucleotide position 3040. The alanine at codon 1014 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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 this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198177	SCV000254078	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1014 of the ATM protein (p.Ala1014Thr). This variant is present in population databases (rs587782163, gnomAD 0.04%). 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: 141992). 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. 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	RCV000130755	SCV000292208	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1014 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 ATM-related disorders in the literature. This variant has been identified in 14/251184 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.
Genetic Services Laboratory, University of Chicago	RCV001818317	SCV002069481	uncertain significance	not specified	2018-09-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000198177	SCV003827459	uncertain significance	Ataxia-telangiectasia syndrome	2022-01-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467154	SCV004209441	uncertain significance	Familial cancer of breast	2023-11-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000198177	SCV002076581	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551257	SCV004120767	uncertain significance	ATM-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The ATM c.3040G>A variant is predicted to result in the amino acid substitution p.Ala1014Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141992/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.