Submissions for variant NM_000051.4(ATM):c.589G>A (p.Gly197Arg)

dbSNP: rs764080545

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217038	SCV000274532	uncertain significance	Hereditary cancer-predisposing syndrome	2015-03-15	criteria provided, single submitter	clinical testing	The p.G197R variant (also known as c.589G>A), located in coding exon 5 of the ATM gene, results from a G to A substitution at nucleotide position 589. The glycine at codon 197 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6497 samples (12994 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 41000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.G197R remains unclear.
GeneDx	RCV000235397	SCV000293593	uncertain significance	not provided	2015-11-24	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.589G>A at the cDNA level, p.Gly197Arg (G197R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Gly197Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Gly197Arg occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Gly197Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069719	SCV001234909	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 197 of the ATM protein (p.Gly197Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs764080545, ExAC 0.002%). 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: 230853). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Baylor Genetics	RCV004567537	SCV005056898	uncertain significance	Familial cancer of breast	2024-03-09	criteria provided, single submitter	clinical testing