ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779872
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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV001197256 SCV004565390 likely pathogenic Familial cancer of breast 2024-01-25 reviewed by expert panel curation The c.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting)
GeneDx RCV000212084 SCV000149174 pathogenic not provided 2023-05-24 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced ATM protein levels and reduced or absent ATM kinase activity (Becker-Catania et al., 2000; Sun et al., 2002; Butch et al., 2004; Chun and Gatti, 2004; Barone et al., 2009; Mitui et al., 2009; Reiman et al., 2011; Fievet et al., 2019; Schon et al., 2019); Observed in the heterozygous state in individuals with ATM-related cancers (Schroeder et al., 2015; Hansen et al., 2017; Renault et al., 2018; Girard et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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: 15503472, 25793145, 9443866, 16448697, 29665859, 32980694, 29922827, 28888541, 12673797, 12072877, 20301790, 23091097, 15486025, 19431188, 10817650, 25040471, 12497634, 18634022, 15279807, 27135926, 26681312, 26312527, 26022348, 28008555, 28195393, 12552559, 22529920, 25827173, 30093976, 30549301, 31050087, 21792198, 22017321, 23532176, 29625052, 30875412, 35264596, 34926252, 35737913, 33328602, 35486574, 33471991, 32155193, 36988593, 35454905, 35365198, 36521553, 26896183, 26846839, 21665257, 10873394, 30303537)
Ambry Genetics RCV000115265 SCV000186811 pathogenic Hereditary cancer-predisposing syndrome 2021-12-17 criteria provided, single submitter clinical testing The p.R2832C pathogenic mutation (also known as c.8494C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8494. The arginine at codon 2832 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in many ataxia-telangiectasia (A-T) patients (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). Functional analyses of p.R2832C have shown abolished kinase activity, reduced protein levels, and increased radiosensitivity compared to wild type ATM. In addition, four of five mild A-T patients carrying this alteration developed cancer, including breast cancers, melanoma, and hematologic malignancies. Three of four p.R2832C carrier mothers from these families developed breast cancer (Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). It was also seen in a patient with a personal and family history of colorectal cancer (Hansen MF et al. Clin. Genet. 2017 Oct;92:405-414). Of note, this alteration is also designated as R2831C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000169354 SCV000220724 likely pathogenic Ataxia-telangiectasia syndrome 2014-09-23 criteria provided, single submitter literature only
Invitae RCV000169354 SCV000260807 pathogenic Ataxia-telangiectasia syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2832 of the ATM protein (p.Arg2832Cys). This variant is present in population databases (rs587779872, gnomAD 0.01%). This missense change has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 9443866, 10817650, 10873394, 12552559, 18634022, 26681312). ClinVar contains an entry for this variant (Variation ID: 127459). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 10873394, 19431188). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000115265 SCV000682491 pathogenic Hereditary cancer-predisposing syndrome 2021-06-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 2832 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). Functional studies have shown that this variant results in significantly reduced ATM protein expression and kinase activity, and intermediate radiosensitivity (PMID: 10873394, 18634022, 19431188, 22017321). This variant has also been observed homozygous or in compound heterozygous state with another pathogenic variant in individuals affected with ataxia-telangiectasia (PMID: 9443866, 10817650, 10873394, 12552559, 12673797, 18634022, 19147735, 19431188, 21792198, 22017321). This variant has also been reported in individuals affected with breast cancer (PMID: 18634022, 20301790, 26022348, 26681312, 28008555, 29665859, 30093976). This variant has been identified in 8/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000169354 SCV000809109 pathogenic Ataxia-telangiectasia syndrome 2018-07-10 criteria provided, single submitter clinical testing
Mendelics RCV000169354 SCV000838615 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001197256 SCV001367893 likely pathogenic Familial cancer of breast 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP4,PP3.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000115265 SCV001448937 pathogenic Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001197256 SCV001499612 likely pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814061 SCV001755356 pathogenic Abnormal central motor function 2021-07-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000169354 SCV002020837 pathogenic Ataxia-telangiectasia syndrome 2019-06-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115265 SCV002527352 pathogenic Hereditary cancer-predisposing syndrome 2021-07-23 criteria provided, single submitter curation
Lifecell International Pvt. Ltd RCV000169354 SCV003923315 pathogenic Ataxia-telangiectasia syndrome criteria provided, single submitter clinical testing A Homozygote Missense variant c.8494C>T in Exon 58 of the ATM gene that results in the amino acid substitution p.Arg2832Cys was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic. (Variation ID: 127459). The variant has been previously reported for Ataxia-Telangiectasia by Telatar M, et al., 1988. Experimental study revealed the missense variant affects the protein function (Mitui M, et al., 2009). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
CeGaT Center for Human Genetics Tuebingen RCV000212084 SCV004042529 likely pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing ATM: PM1, PM2, PM5, PS3:Moderate, BP1
Baylor Genetics RCV001197256 SCV004209520 pathogenic Familial cancer of breast 2023-09-02 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001197256 SCV004933083 likely pathogenic Familial cancer of breast 2024-02-02 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18634022, 21792198]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21665257].
GeneReviews RCV000169354 SCV000328272 not provided Ataxia-telangiectasia syndrome no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212084 SCV001963400 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000212084 SCV001968972 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000169354 SCV002082548 pathogenic Ataxia-telangiectasia syndrome 2018-01-05 no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162536 SCV002758111 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences RCV000169354 SCV003936079 pathogenic Ataxia-telangiectasia syndrome no assertion criteria provided research

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