Submissions for variant NM_000051.4(ATM):c.7522G>A (p.Gly2508Arg)

gnomAD frequency: 0.00001  dbSNP: rs754395517

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166982	SCV000217803	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	The p.G2508R variant (also known as c.7522G>A), located in coding exon 50 of the ATM gene, results from a G to A substitution at nucleotide position 7522. The glycine at codon 2508 is replaced by arginine, an amino acid with dissimilar properties. This variant was 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 amino acid position is not well 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.
GeneDx	RCV000235394	SCV000292482	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with prostate, colorectal, or other cancers (Lu et al., 2015; Yurgelun et al., 2015; Duzkale et al., 2021; Karlsson et al., 2021); This variant is associated with the following publications: (PMID: 25980754, 26689913, 26757417, 34271781, 23532176, 33436325)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461205	SCV000547137	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2508 of the ATM protein (p.Gly2508Arg). This variant is present in population databases (rs754395517, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or prostate cancer (PMID: 25980754, 33436325). ClinVar contains an entry for this variant (Variation ID: 187265). 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.
Color Diagnostics, LLC DBA Color Health	RCV000166982	SCV000682423	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2508 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 been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), an individual affected with prostate cancer (PMID: 33436325), and an individual affected with colorectal cancer (PMID: 34271781). In a large international case-control study, this variant was reported in 11/60466 breast cancer cases and 4/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/281930 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.
PreventionGenetics, part of Exact Sciences	RCV004552929	SCV004113340	uncertain significance	ATM-related disorder	2023-08-01	criteria provided, single submitter	clinical testing	The ATM c.7522G>A variant is predicted to result in the amino acid substitution p.Gly2508Arg. This variant has been identified in an individual undergoing Lynch syndrome-testing (Yurgelun et al. 2015. PubMed ID: 25980754, Table S2), an individual with glioblastoma multiforme (Lu et al. 2015. PubMed ID: 26689913, Table S12), and an individual with prostate cancer (Karlsson et al. 2021. PubMed ID: 33436325, Table S4). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108202177-G-A) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187265/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000235394	SCV004133274	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ATM: BP4
Baylor Genetics	RCV004567324	SCV005057045	uncertain significance	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing
Mendelics	RCV004698829	SCV005200752	uncertain significance	Hereditary cancer	2024-08-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000461205	SCV002080699	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-21	no assertion criteria provided	clinical testing