Submissions for variant NM_000051.4(ATM):c.2414G>A (p.Arg805Gln)

gnomAD frequency: 0.00003  dbSNP: rs587782255

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130968	SCV000185883	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-20	criteria provided, single submitter	clinical testing	The p.R805Q variant (also known as c.2414G>A), located in coding exon 15 of the ATM gene, results from a G to A substitution at nucleotide position 2414. The arginine at codon 805 is replaced by glutamine, an amino acid with highly similar properties. This variant has been previously detected in breast cancer patients (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Tung N et al. Cancer, 2015 Jan;121:25-33). This variant has also been reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This alteration has been reported in the germline of 1 of 8,920 ethnically matched normal population control subjects but was not seen in 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). 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.
Invitae	RCV000466366	SCV000546780	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 805 of the ATM protein (p.Arg805Gln). This variant is present in population databases (rs587782255, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 17393301, 19781682, 33436325). ClinVar contains an entry for this variant (Variation ID: 142128). 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 tolerated. 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	RCV000482755	SCV000564618	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer (Broeks et al., 2008; Tavtigian et al., 2009; Tung et al., 2015; Karlsson et al., 2021); This variant is associated with the following publications: (PMID: 25186627, 17393301, 20224443, 19781682, 27311873, 30197789, 33436325)
Color Diagnostics, LLC DBA Color Health	RCV000130968	SCV000903406	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 805 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 4/53457 controls (PMID: 33471991). This variant has been reported in several individuals affected with breast cancer (PMID: 17393301, 19781682). This variant has been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic BRCA1 variant (Color internal data). This variant has been identified in 7/251236 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.
Fulgent Genetics, Fulgent Genetics	RCV002492510	SCV002794027	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-27	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338419	SCV004048517	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense variant in c.2414G>A (p.Arg805Gln) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg805Gln variant is reported with the allele frequency of 0.002786% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as uncertain significance. The amino acid Arg at position 805 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Arg805Gln in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Baylor Genetics	RCV003338419	SCV004209546	uncertain significance	Familial cancer of breast	2023-08-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000482755	SCV004229169	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000482755	SCV001739570	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000482755	SCV001906039	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000466366	SCV002077762	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-17	no assertion criteria provided	clinical testing