Submissions for variant NM_000051.4(ATM):c.6412A>G (p.Arg2138Gly)

gnomAD frequency: 0.00001  dbSNP: rs752069869

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213307	SCV000275304	uncertain significance	Hereditary cancer-predisposing syndrome	2016-07-28	criteria provided, single submitter	clinical testing	The p.R2138G variant (also known as c.6412A>G), located in coding exon 43 of the ATM gene, results from an A to G substitution at nucleotide position 6412. The arginine at codon 2138 is replaced by glycine, 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 6495 samples (12990 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 180000 alleles tested) in our clinical cohort. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791592	SCV000930849	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2138 of the ATM protein (p.Arg2138Gly). This variant is present in population databases (rs752069869, gnomAD 0.007%). 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: 231452). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225521	SCV002504751	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462463	SCV004215519	uncertain significance	Familial cancer of breast	2023-05-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213307	SCV004361797	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2138 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 3/249536 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.
Natera, Inc.	RCV000791592	SCV002084297	uncertain significance	Ataxia-telangiectasia syndrome	2019-10-28	no assertion criteria provided	clinical testing