Submissions for variant NM_000051.4(ATM):c.590G>A (p.Gly197Glu)

gnomAD frequency: 0.00003  dbSNP: rs753806542

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482564	SCV000568313	uncertain significance	not provided	2021-05-17	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: reduced ATM protein levels, but retained kinase activity (Carrillo 2009); Observed as apparently homozygous in an individual with a pharyngeal telangiectasia and dystonia with onset at 15 years old and in two consanguineous siblings with ataxia, global developmental delay, and hypotonia (Carrillo 2009, Cordeiro 2018, Schon 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23143971, 18846412, 25040471, 28779002, 30283815, 30549301)
Ambry Genetics	RCV000569534	SCV000667821	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	The p.G197E variant (also known as c.590G>A), located in coding exon 5 of the ATM gene, results from a G to A substitution at nucleotide position 590. The glycine at codon 197 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported as homozygous in a patient with atypical ataxia-telangiectasia (A-T) whose primary presentation was dystonia at age 15 years (Carrillo F et al. Cerebellum. 2009 Mar;8(1):22-7). A lymphoblastoid cell line derived from the patient's blood showed a reduced level of ATM protein; the ATM protein retained some kinase activity in vivo. This alteration has also been reported as homozygous in two siblings who presented with global developmental delay and ataxia (Cordeiro D et al. Neurol Genet, 2018 Oct;4:e265). Additionally, this alteration was identified in the homozygous state in an individual with a clinical diagnosis of of A-T (Kim J et al. Nature, 2023 Jul;619:828-836). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569534	SCV000913532	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 197 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported in homozygosity in an individual affected with a mild form of ataxia telangiectasia (PMID: 18846412). A lymphoblastoid cell line derived from this pronand showed a partially reduced ATM protein expression and kinase activity (PMID: 18846412). This variant has been observed in an healthy control individual in a breast cancer case-control study (PMID 28779002). This variant has been identified in 7/250934 chromosomes (7/30596 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in hereditary cancer conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806962	SCV000946986	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 197 of the ATM protein (p.Gly197Glu). This variant is present in population databases (rs753806542, gnomAD 0.02%). This missense change has been observed in individual(s) with atypical ataxia-telangiectasia (PMID: 18846412). ClinVar contains an entry for this variant (Variation ID: 420008). 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 disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 18846412). 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000806962	SCV002098314	likely pathogenic	Ataxia-telangiectasia syndrome	2021-10-29	criteria provided, single submitter	clinical testing	A homozygous missense variation in exon 6 of the ATM gene that results in the amino acid substitution of Glutamic acid for Glycine at codon 197 was detected. The observed variant c.590G>A (p.Gly197Glu) has not been reported in the 1000 genomes and gnomAD database. The in silico prediction of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, MutationTaster2 and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a likely pathogenic variant.
Baylor Genetics	RCV003470549	SCV004212210	uncertain significance	Familial cancer of breast	2022-09-26	criteria provided, single submitter	clinical testing