Submissions for variant NM_000051.4(ATM):c.8330G>T (p.Gly2777Val)

dbSNP: rs879254240

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236765	SCV000293936	uncertain significance	not provided	2016-02-11	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8330G>T at the cDNA level, p.Gly2777Val (G2777V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Gly2777Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. ATM Gly2777Val occurs at a position that is conserved across species and is located in the PI3-PI4 kinase domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Gly2777Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000569573	SCV000665196	uncertain significance	Hereditary cancer-predisposing syndrome	2016-07-07	criteria provided, single submitter	clinical testing	The p.G2777V variant (also known as c.8330G>T), located in coding exon 56 of the ATM gene, results from a G to T substitution at nucleotide position 8330. The glycine at codon 2777 is replaced by valine, 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 6499 samples (12998 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 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 this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569573	SCV001345912	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2777 of the ATM protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, 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 not been identified 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	RCV002518464	SCV003314243	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 246398). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2777 of the ATM protein (p.Gly2777Val).