Submissions for variant NM_000051.4(ATM):c.1481G>A (p.Gly494Asp)

gnomAD frequency: 0.00001  dbSNP: rs786202233

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164949	SCV000215640	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.G494D variant (also known as c.1481G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1481. The glycine at codon 494 is replaced by aspartic acid, 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	RCV000164949	SCV000681979	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 494 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 3/251286 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.
Counsyl	RCV000669269	SCV000794006	uncertain significance	Ataxia-telangiectasia syndrome	2017-09-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669269	SCV001394044	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 494 of the ATM protein (p.Gly494Asp). This variant is present in population databases (rs786202233, gnomAD 0.02%). 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: 185509). 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	RCV001574162	SCV001800927	uncertain significance	not provided	2020-10-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30942098)
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153443	SCV003843705	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462158	SCV004208252	uncertain significance	Familial cancer of breast	2023-10-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000669269	SCV002095433	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-30	no assertion criteria provided	clinical testing