Submissions for variant NM_000051.4(ATM):c.6424A>G (p.Thr2142Ala)

dbSNP: rs1263398076

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568520	SCV000660504	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	The p.T2142A variant (also known as c.6424A>G), located in coding exon 43 of the ATM gene, results from an A to G substitution at nucleotide position 6424. The threonine at codon 2142 is replaced by alanine, an amino acid with similar 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.
Color Diagnostics, LLC DBA Color Health	RCV000568520	SCV000682335	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2142 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 been identified in 1/249418 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	RCV000820050	SCV000960742	uncertain significance	Ataxia-telangiectasia syndrome	2022-04-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2142 of the ATM protein (p.Thr2142Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 478935). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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.
GeneDx	RCV001591318	SCV001825787	uncertain significance	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176)
Genetic Services Laboratory, University of Chicago	RCV001821656	SCV002067824	uncertain significance	not specified	2019-11-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004569090	SCV005056905	uncertain significance	Familial cancer of breast	2024-03-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000820050	SCV002084330	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-23	no assertion criteria provided	clinical testing