Submissions for variant NM_000051.4(ATM):c.8734A>G (p.Arg2912Gly)

gnomAD frequency: 0.00019  dbSNP: rs376676328

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV001196874	SCV002499283	uncertain significance	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122892	SCV000166150	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	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 2912 of the ATM protein (p.Arg2912Gly). This variant is present in population databases (rs376676328, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer and/or other cancers (PMID: 12810666, 17166884, 21787400, 27443514, 28093616, 28828701, 30814645, 35047863). It has also been observed to segregate with disease in related individuals. This missense change has been observed to co-occur in individuals with a different variant in ATM that has been determined to be pathogenic (PMID: 12810666, 28828701; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 133641). 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. 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.
Ambry Genetics	RCV000131723	SCV000186763	likely benign	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656766	SCV000209663	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	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: 19781682, 24728327, 30613976, 20346647, 21787400, 12673797, 25452441, 27443514, 26976419, 28135145, 28828701, 26787654, 26483394, 28093616, 28779002, 11505391, 12810666, 17166884, 29945567, 30197789, 28652578, 31159747, 32183364, 34426522, 33280026, 33471991, 33436325, 33910496, 34573280, 35047863, 35365198, 35886069, 34761457, 35475445, 36555667, 35029067, 36983044, 34326862, 31882575, Richardson2024[Preprint], 38701358, 38734904, 34262154, 23532176, 35534704)
Color Diagnostics, LLC DBA Color Health	RCV000131723	SCV000292188	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2912 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study reported that the variant may partially affect the kinase activity (PMID: 17166884). This variant has been reported in individuals affected with breast cancer (PMID: 11505391, 12673797, 12810666, 17166884, 21787400, 25452441, 26976419, 28779002, 28828701, 33471991, 35365198; DOI: 10.1186/s12859-021-04144-1), pancreatic cancer (PMID: 26483394, 29945567), colorectal cancer (PMID: 28135145, 30814645, 35029067), prostate cancer (PMID: 32183364, 35886069), endometrial cancer (PMID: 27443514), melanoma (PMID: 36555667), and chronic lymphocytic leukemia (PMID: 28652578). However it has also been observed in healthy individuals and controls (PMID: 21787400, 24728327, 28652578, 33471991). Breast cancer cases in the literature have been reported with pathogenic covariants in other genes (PMID: 12673797, 28828701) and with truncations in ATM (Color internal data). This variant has been identified in 58/282848 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	RCV000515325	SCV000611371	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-23	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000131723	SCV000821881	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000122892	SCV001138585	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000656766	SCV001143127	uncertain significance	not provided	2018-12-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000122892	SCV001264810	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120167	SCV001363783	uncertain significance	not specified	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8734A>G (p.Arg2912Gly) results in a non-conservative amino acid change located in the catalytic domain (IPR044107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 253178 control chromosomes (gnomAD, Renault_2022), including 1 homozygote in the gnomAD database (of note, this individual is not included in the non-neuro dataset). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00029 vs 0.001), allowing no conclusion about variant significance. The variant has also been reported in 2/7325 European American women over the age of 70 with no personal history of cancer (FLOSSIES database). However, the variant c.8734A>G, has also been reported in the literature in numerous individuals affected with Breast and other cancer phenotypes (e.g. Bernstein_2003, Goldgar_2011, Pylkas_2007, Pylkas_2007, Ring_2016, Teraoka_2001, Thorstenson_2003, Thorstenson_2003, Young_2018, Zidan_2017, Rizzolo_2019, Tsaousis_2019, Jarhelle_2019, Rantapero_2020, Feliubadalo_2020, Karlsson_2021, Mikaeel_2022) as well as in an individual with immune deficiency (Grossi_2021). One of these reports demonstrated an incomplete co-segregation with disease, due to its presence in unaffected family members, as well as other affected family members who did not carry this variant (Pylkas_2007). In another report a co-occurrence with a pathogenic variant has been noted (BRCA1 c.68_69delAG, p.Glu23ValfsX17; Thorstenson_2003), providing supporting evidence for a benign role. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 39/60466 cases and in 30/53461 controls (Dorling_2021 through LOVD). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a partial defect in kinase activity, but normal ATM expression and protein stability, no dominant-negative effect and no increased sensitivity to irradiation (Pylkas_2007). The following publications have been ascertained in the context of this evaluation (PMID: 12673797, 25452441, 33471991, 33280026, 21787400, 34573280, 31882575, 33436325, 34761457, 17166884, 32183364, 35365198, 27443514, 30613976, 11505391, 12810666, 31159747, 29945567, 28828701). Multiple ClinVar submitters have assessed the variant since 2014 with a predominant consensus as VUS and some submitters citing overlapping evidence utilized in the context of this evaluation (VUS, n=19; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196874	SCV001367508	uncertain significance	Familial cancer of breast	2019-12-12	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000131723	SCV001911490	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.8734A>G (p. Arg2912Gly) variant has an allele frequency of 0.00020 (0.02%, 54/268,310 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00039 (0.04%, 46/118,146 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). It is located in the PI3K domain, whose important role is highlighted by the fact that no missense variants with a minor allele frequency greater than 0.05% have been described in it (PM1_Supporting). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 + PM1_Supporting (PMID: 33280026).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656766	SCV002010776	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120167	SCV002067149	uncertain significance	not specified	2020-09-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.8734A>G, in exon 60 that results in an amino acid change, p.Arg2912Gly. This sequence change has been described in the gnomAD database with a frequency of 0.039% in the European sub-population (dbSNP rs376676328). The p.Arg2912Gly change has been reported in an individual with endometrial cancer (PMID: 27443514), an individual with prostate cancer (PMID: 29945567), and families with breast cancer (PMID: 11505391, 12810666, 17166884). However, the p.Arg2912Gly change has also been observed in a family with a pathogenic BRCA1 variant (PMID: 12810666) and has shown incomplete segregation with the cancer phenotype in two breast cancer kindreds (PMID: 17166884). An in vitro functional study demonstrated that the p.Arg2912Gly change does not impact protein stability, but partially impacts ATM kinase activity (PMID: 17166884). The p.Arg2912Gly change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2912Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Arg2912Gly change remains unknown at this time.
Sema4, Sema4	RCV000131723	SCV002527942	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000656766	SCV002541172	uncertain significance	not provided	2021-11-12	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001196874	SCV002580925	uncertain significance	Familial cancer of breast	2022-07-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120167	SCV002760710	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656766	SCV003800431	uncertain significance	not provided	2022-04-19	criteria provided, single submitter	clinical testing	The ATM c.8734A>G; p.Arg2912Gly variant (rs376676328), is reported in the literature in individuals affected with various forms of suspected hereditary cancer and suspected immunodeficiency (selected references: Teraoka 2001, Goldgar 2011, Young 2011, and Grossi 2021). However it has also been reported in trans with a pathogenic variant in individuals without signs of ataxia-telangiectasia (ClinGen VCEP). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (50 / 129,162 alleles, including 1 homozygotes) in the Genome Aggregation Database. The arginine at codon 2912 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.88). Due to conflicting information, the clinical significance of the p.Arg2912Gly variant is uncertain at this time. REFERENCES: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP: https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2560f0e1-9f2c-47aa-bea7-48edcf90c9a7 Goldgar et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. PMID: 21787400. Grossi et al. Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. Genes (Basel). 2021 Aug 24;12(9):1299. PMID: 34573280. Teraoka et al. Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer. 2001 Aug 1;92(3):479-87. PMID: 11505391. Young et al. Pancreatic cancer as a sentinel for hereditary cancer predisposition. BMC Cancer. 2018 Jun 27;18(1):697. doi: 10.1186/s12885-018-4573-5. PMID: 29945567.
Baylor Genetics	RCV001196874	SCV004206344	uncertain significance	Familial cancer of breast	2024-03-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656766	SCV004222291	uncertain significance	not provided	2018-12-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast (PMIDs: 33471991 (2021), 33280026 (2021), 31159747 (2019), 31882575 (2019), 28828701 (2017), 26976419 (2016), 11505391 (2001)), endometrial (PMID: 27443514 (2016)), pancreatic (PMID: 29945567 (2018)), prostate (PMID: 35886069 (2022)), or colorectal cancer (PMIDs: 34761457 (2022) and 30814645 (2019)), as well as melanoma (PMID: 36555667 (2022)). It has also been described in unaffected controls (PMIDs: 33471991 (2021) and 35365198 (2022)). The association of the variant with disease in different families is inconclusive (PMIDs 17166884 (2007) and 21787400 (2011)). In breast tumor sample, however, this variant was not identified as a driver of malignancy per LOH of the variant (PMID: 21787400 (2011)). Functional studies determined that this variant caused only a partial defect in ATM kinase activity upon CHEK1, however, other kinase targets studied as well as ATM protein expression and stability, were not affected (PMID: 17166884 (2007)). The frequency of this variant in the general population, 0.00039 (50/129162 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492518	SCV004239605	uncertain significance	Breast and/or ovarian cancer	2023-03-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656766	SCV005050351	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ATM: PP3
Myriad Genetics, Inc.	RCV001196874	SCV005084048	likely benign	Familial cancer of breast	2024-06-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
ITMI	RCV000120167	SCV000084309	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000122892	SCV001452579	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355184	SCV001549991	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Arg2912Gly variant was identified in 7 of 8092 proband chromosomes (frequency: 0.0009) from Finnish (BRCA1/2 negative), Austrian, and American individuals or families with HBOC or breast cancer and was not identified in 7520 control chromosomes from healthy and unselected individuals (Tung 2016, Thorstenson 2003, Teraoka 2001, Pylkas 2007). In one study, 1 affected individual had the variant cooccurring with a pathogenic BRCA1 mutation (185delAG, 39stop) (Thorstenson 2003). In another study, segregation of the variant with cancer was not shown as several unaffected carriers occurred in the families of both positive cases (Pylkas 2007). Additionally, functional assays using LCL (lymphblastoid cell lines) demonstrated the variant to have similar protein expression levels to wildtype, and a partial defect in the phosphorylation of ATM substrates (Pylkas 2007). The variant was also identified in dbSNP (ID: rs376676328) “With Uncertain significance allele”, ClinVar (classified as uncertain significance; submitters: Invitae, Ambry Genetics, GeneDx, Color Genomics; and classification not provided by ITMI), Clinvitae (3x), and in control databases in 61 (1 homozygous) of 277204 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: Other in 1 of 6466 chromosomes (frequency: 0.0002), Latino in 1 of 34420 chromosomes (frequency: 0.00003), European Non-Finnish in 53 (1 homozygous) of 126696 chromosomes (frequency: 0.0004), Ashkenazi Jewish in 4 of 10150 chromosomes (frequency: 0.0004), European Finnish in 1 of 25794 chromosomes (frequency: 0.00004), and South Asian in 1 of 30782 chromosomes (frequency: 0.00003). The variant was not identified in Cosmic, MutDB, LOVD 3.0, ATM-LOVD, and GeneInsight – COGR (unavailable). The p.Arg2912 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
GenomeConnect - Invitae Patient Insights Network	RCV000515325	SCV004228950	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-13-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004551182	SCV004747187	uncertain significance	ATM-related disorder	2023-12-18	no assertion criteria provided	clinical testing	The ATM c.8734A>G variant is predicted to result in the amino acid substitution p.Arg2912Gly. The Arg2912 residue, located within the kinase domain of the ATM protein, has been highly conserved during evolution. This variant has been reported with a frequency of 0.038% among European (non-Finnish) individuals of unknown phenotype (including one homozygous individual) in a large population database, and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133641/). This variant has also been reported in multiple individuals with personal or family history of breast cancer (Teraoka et al. 2001, PubMed ID: 11505391; Thorstenson et al. 2003, PubMed ID: 12810666; Goldgar et al. 2011, Table S1, PubMed ID: 21787400; Couch et al. 2015, Table S6, PubMed ID: 25452441) and colorectal cancer (Yurgelun et al. 2017, PubMed ID: 28135145). However, Pylkäs et al. has reported incomplete segregation of this variant with familial breast cancer (Pylkäs et al. 2007, PubMed ID: 17166884). These authors further functionally demonstrated that the p.Arg2912Gly variant does not impair the phosphorylation of all the ATM substrates, indicating that a dominant-negative effect is unlikely for this variant. Taken together, although there is a possibility that the p.Arg2912Gly variant may impair protein-protein interactions associated with optimal ATM activity, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.