ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8122G>A (p.Asp2708Asn) (rs587782719)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132208 SCV000187290 pathogenic Hereditary cancer-predisposing syndrome 2020-10-13 criteria provided, single submitter clinical testing The p.D2708N pathogenic mutation(also known as c.8122G>A), located in coding exon 54 of the ATM gene, results from a G to A substitution at nucleotide position 8122. The aspartic acid at codon 2708 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in conjunction with other pathogenic ATM mutations (phase confirmed in two cases) in several individuals with classic and variant ataxia telangiectasia (AT) (Micol R et al. J. Allergy Clin. Immunol. 2011;128(2):382-9; Claes K et al. Neuromolecular Med. 2013;15(3):447-57; Cavalieri S et al. Ann. Hum. Genet. 2008;72(Pt 1):10-8; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64). In two studies, this alteration was shown to demonstrate a significant reduction in ATM protein expression and kinase activity, as well as mislocalization of the protein (Jacquemin V et al. Eur. J. Hum. Genet. 2012;20(3):305-12; Barone G et al. Hum. Mutat. 2009;30(8):1222-30). In addition, a disease-causing mutation, p.D2708E, has been described at the same codon (Heinrich T et al. Eur. J. Pediatr. 2006; 165:250-7; Bisgin A et al. Biomed Res Int 2018 May;2018:9647253, Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9.e1; Jacquemin V et al. Eur. J. Hum. Genet. 2012; 20:305-12.). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000255899 SCV000322142 likely pathogenic not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.8122G>A at the cDNA level, p.Asp2708Asn (D2708N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been observed in the compound heterozygous state in association with classic and variant forms of ataxia-telangiectasia (Cavalieri 2006, Magliozzi 2006, Jacquemin 2012, Claes 2013, Leuzzi 2018). In addition, this variant was observed in the heterozygous state in an individual with T-cell prolymphocytic leukemia, an individual with breast cancer, and an individual with ovarian and bilateral breast cancer (Reiman 2011, Decker 2017, Tavera-Tapia 2017). Functional studies have shown that ATM Asp2708Asn results in reduced ATM protein expression, reduced kinase activity, and increased radiosensitivity when compared to wild type (Barone 2009, Claes 2013, Jacquemin 2012). ATM Asp2708Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider ATM Asp2708Asn to be a likely pathogenic variant.
Invitae RCV000559678 SCV000622801 pathogenic Ataxia-telangiectasia syndrome 2020-08-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 2708 of the ATM protein (p.Asp2708Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as biallelic with other pathogenic ATM variants in the literature in multiple individuals affected with ataxia telangiectasia (A-T) (PMID: 16941484, 22071889, 23454770, 23632773, 21665257), an individual affected with A-T and T-cell-prolymphocytic leukaemia and thyroid carcinoma (PMID: 21792198) and as heterozygous in individuals affected with embryonal rhabdomyosarcoma, and breast and ovarian cancer (PMID: 23632773, 27913932). In addition, it has been reported in the unaffected father of an individual affected with A-T (PMID: 23632773). ClinVar contains an entry for this variant (Variation ID: 142791). Experimental studies have shown that this missense change (p.Asp2708Asn) results in reduced ATM protein expression and kinase activity (PMID: 22071889, 19431188, 23454770, 23632773) and increased radiosensitivity in cells carrying the variant (PMID: 23632773). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000559678 SCV000800801 likely pathogenic Ataxia-telangiectasia syndrome 2018-01-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255899 SCV000883423 likely pathogenic not provided 2018-06-24 criteria provided, single submitter clinical testing The ATM c.8122G>A; p.Asp2708Asn variant (rs587782719), is reported in the literature in a compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (A-T; Cavalieri 2006, Claes 2013, Jacquemin 2012, Magliozzi 2006, Prodosmo 2013, Reiman 2011) and one heterozygous individual with bilateral breast cancer and ovarian cancer (Tavera-Tapia 2017). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 142791), and is also largely absent from general population databases (not found in 1000 Genomes Project or Exome Variant Server, and one heterozygous individual in Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 2708 is highly conserved, and functional analyses of the variant protein show reduced kinase activity and increased radiosensitivity (Barone 2009, Claes 2013, Jacquemin 2012). Based on available information, this variant is considered to be likely pathogenic. Pathogenic variants in the ATM gene follow an autosomal recessive inheritance pattern and are associated with ataxia-telangiectasia (A-T; MIM: 208900), and an autosomal dominant inheritance pattern and are associated with an increased risk for breast cancer (MIM: 114480). References: Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-30. Cavalieri S et al. ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions. Hum Mutat. 2006 Oct;27(10):1061. Claes K et al. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives. Neuromolecular Med. 2013 Sep;15(3):447-57. Jacquemin V et al. Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet. 2012 Mar;20(3):305-12. Magliozzi M et al. DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations. Dis Markers. 2006;22(4):257-64. Prodosmo A et al. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes. J Clin Invest. 2013 Mar;123(3):1335-42. doi: 10.1172/JCI67289. Epub 2013 Feb 1. Reiman A et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br J Cancer. 2011 Aug 9;105(4):586-91. Tavera-Tapia A et al. Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene. Breast Cancer Res Treat. 2017 Feb;161(3):597-604.
Color Health, Inc RCV000132208 SCV000911719 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000132208 SCV000992206 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Mendelics RCV000559678 SCV001138576 likely pathogenic Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000132208 SCV001911487 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.8122G>A (p.Asp2708Asn) variant appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the South-Asian subpopulation (PM2; 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 has been described in trans with the pathogenic ATM variant c.2250G>A in two ataxia-telangiectasia probands and together (unknown phase) with the pathogenic ATM variant c.3712_3716del in another ataxia-telangiectasia proband, which awards 2.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_Strong; PMID: 22071889, 16941484, 17124347). Studies in ataxia-telangiectasia patient carrier cells show no autophosphorilation in Serine 1981 and no (or trace) phosphorylation of 4 substrates upon irradiation, confirmed with two substrates by functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line. Intermediate irradiation sensitivity was found in a micronuclei assay (PS3_Moderate; PMID: 22071889, 23632773, 19431188). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules were applied as defined by the Spanish-ATM Variant Curation Panel: PM2 + PP3 + PM3_Strong + PS3_Moderate. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 (PMID: 33280026).

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