Submissions for variant NM_000051.4(ATM):c.989G>C (p.Gly330Ala)

gnomAD frequency: 0.00001  dbSNP: rs762179829

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561901	SCV000668020	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	The p.G330A variant (also known as c.989G>C), located in coding exon 7 of the ATM gene, results from a G to C substitution at nucleotide position 989. The glycine at codon 330 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000561901	SCV001344529	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 330 of the ATM protein. Computational prediction tool 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 not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251172 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	RCV001238128	SCV001410927	uncertain significance	Ataxia-telangiectasia syndrome	2022-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 330 of the ATM protein (p.Gly330Ala). This variant is present in population databases (rs762179829, 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: 482661). 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	RCV002281114	SCV002569823	uncertain significance	not provided	2022-08-29	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
Baylor Genetics	RCV004569193	SCV005056956	uncertain significance	Familial cancer of breast	2024-02-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001238128	SCV002089637	uncertain significance	Ataxia-telangiectasia syndrome	2019-10-28	no assertion criteria provided	clinical testing