ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.9022C>T (p.Arg3008Cys) (rs587782292)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131173 SCV000186119 pathogenic Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing The p.R3008C pathogenic mutation (also known as c.9022C>T) is located in coding exon 62 of the ATM gene. This alteration results from a C to T substitution at nucleotide position 9022. The arginine at codon 3008 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported both in trans with pathogenic splice site mutations and also homozygous in a patient with classic ataxia-telangiectasia (Hacia J et al. Genome Res. 1998 Dec; 8(12):1245-58; Li A and Swift M. Am J Hum Genet. 2000 May 29; 92(3):170-7; Angele S et al. Hum Mutat. 2003 Feb; 21(2):169-70). A study of 104 Irish cases of hereditary breast cancer identified this alteration in one case (Aloraifi F et al., FEBS J. 2015 Sep; 282(17):3424-37). This alteration was also identified in 1 individual with breast cancer in a study of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). This alteration impacts a highly-conserved residue in the ATM kinase domain and functional studies of this alteration have demonstrated complete loss of kinase activity both in vitro and in vivo (Angele S et al. Hum Mutat. 2003 Feb; 21(2):169-70). In addition, p.R3008C has been associated with reduced ATM protein levels, radiosensitivity levels similar to truncating mutations, and interference with endogenous ATM protein (Gutierrez-Enriquez S et al. Genes Chromosomes Cancer. 2004 Jun; 40(2):109-19; Barone G et al. Hum Mutat. 2009 Aug; 30(8):1222-30). Another missense alteration at this codon (p.R3008H) has been described as a likely deleterious allele detected in 1/122 familial breast cancer cases, 0/186 healthy control samples (Paglia L et al. Breast Cancer Res Treat. 2010 Jan; 119(2):443-52). Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000212096 SCV000209774 pathogenic not provided 2021-04-19 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect showing loss of ATM kinase activity (Angele et al., 2003; Austen et al., 2008; Barone et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in at least one individual with familial breast cancer in published literature (Aloraifi et al., 2015); This variant is associated with the following publications: (PMID: 26354930, 29117359, 28580595, 29038235, 29625052, 19431188, 26094658, 21792198, 21933854, 15101044, 22529920, 16014569, 23585524, 18573109, 16189143, 10817650, 22649200, 27479817, 27542854, 21459046, 25480502, 9872980, 26681312, 29482223, 28767289, 30549301, 32832836, 12552566)
Counsyl RCV000169274 SCV000220577 likely pathogenic Ataxia-telangiectasia syndrome 2014-08-06 criteria provided, single submitter literature only
Invitae RCV000169274 SCV000259422 pathogenic Ataxia-telangiectasia syndrome 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3008 of the ATM protein (p.Arg3008Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782292, ExAC 0.01%). This variant has been reported in individuals affected with ataxia-telangiectasia (A-T), as homozygous as well as compound heterozygous with a second pathogenic ATM variant in trans (PMID: 9872980, 10817650, 12552566, 30549301). This variant has also been reported in an individual with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 142187). Experimental studies have shown that this missense change results in inactivation of ATM kinase activity, increased radio-sensitivity, and cell cycle defects in vitro (PMID: 12552566, 15101044, 18573109). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000131173 SCV000687871 pathogenic Hereditary cancer-predisposing syndrome 2020-06-22 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 3008 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional study found the variant protein to be defective in ATM kinase activity and cellular response to ionizing radiation exposure (PMID: 12552566, 18573109, 19431188). This variant has been observed in homozygous and compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (PMID: 9872980, 10817650, 12552566, 18573109, 21459046, 21792198). This variant also has been observed in three individuals affected with breast cancer (PMID: 26681312, 30128536) and another individual at high-risk for breast and ovarian cancer (PMID: 26094658). This variant has been identified in 4/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Mendelics RCV000169274 SCV000838622 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000212096 SCV001879613 pathogenic not provided 2020-11-04 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity ( This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abolishes the protein's kinase activity (PMID: 19431188, 18573109). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212096 SCV001551150 pathogenic not provided no assertion criteria provided clinical testing The ATM p.Arg3008Cys variant was identified in 3 of 1508 proband chromosomes (frequency: 0.002) from individuals or families with AtaxiaTelangiectasia and CLL (Navrkalova 2013, Reiman 2011, Skowronska 2012). The variant was also identified in ClinVar (classified as pathogenic by Ambry genetics, GeneDx, Invitae; classified as likely pathogenic by Counsyl), Cosmic (classified as pathogenic), MutDB, and ATM-LOVD databases. The variant was not identified in Genesight-COGR, and LOVD 3.0 databases. The variant was identified in control databases in 4 of 246188 chromosomes at a frequency of 0.000016 in the following populations: African in 1 of 15304 chromosomes (freq. 0.00006), East Asian in 1 of 17244 chromosomes (freq. 0.00006), European (Non-Finnish) in 2 of 111646 chromosomes (freq. 0.00002), but not seen in Ashkenazi Jewish, European (Finnish), Latino, South Asian or other populations increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The p.Arg3008 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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. The variant is located with the Phosphatidylinositol 3-/4-kinase, catalytic functional domain increasing the likelihood that it may have clinical significance. In addition, several studies reported the expressed R3008C mutant ATM protein showed absence of ATM kinase activity, and strongly suggest that the 9022C>T (R3008C) missense mutation is the disease causing mutation (Angele 2003, Austen 2008,). The Taylor (2005) identified this variant in homozygous state with total absence of ATM kinase activity, although the amount of ATM protein expressed was about half that of normal cells. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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