rs587782719
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.8122G>A(p.Asp2708Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2708Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8122G>A | p.Asp2708Asn | missense_variant | 55/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8122G>A | p.Asp2708Asn | missense_variant | 55/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251356Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461808Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727196
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 09, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2708 of the ATM protein (p.Asp2708Asn). This variant is present in population databases (rs587782719, gnomAD 0.003%). This missense change has been observed in individuals with ataxia telangiectasia (A-T) and/or cancer (PMID: 16941484, 21665257, 21792198, 22071889, 23454770, 23632773, 27913932, 29909963). ClinVar contains an entry for this variant (Variation ID: 142791). 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: 19431188, 22071889, 23454770, 23632773). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2022 | 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Likely pathogenic, criteria provided, single submitter | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 25, 2021 | This missense variant replaces aspartic acid with asparagine at codon 2708 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 studies have shown that this variant results in reduced ATM kinase activity (PMID: 19431188). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 16941484, 17124347, 17910737, 19431188, 21665257, 21792198, 22071889, 23632773, 25122203, 30338439). It has been reported that cells derived from some of these individuals display reduced kinase activity, protein expression and irradiation response and increased radiosensitivity (PMID: 22071889, 23632773). This variant has also been reported in individuals affected with breast cancer (PMID: 27913932, 28779002). This variant has been identified in 1/251356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | 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). - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2022 | 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: 19431188, 17124347, 22071889, 27913932, 17910737, 16941484, 23632773, 21792198, 29600275, 29909963, 27304073, 28779002, 23454770, 33436325, 29922827, 32980694, 33280026) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 24, 2018 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 01, 2024 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 21665257, 17910737]. Functional studies indicate this variant impacts protein function [PMID: 22071889,19431188, 23632773]. - |
Breast and/or ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 03, 2023 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Familial prostate carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 28, 2023 | Variant summary: ATM c.8122G>A (p.Asp2708Asn) results in a conservative amino acid change located in the catalytic domain (IPR044107) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 (i.e., 1 heterozygote) in 251356 control chromosomes (gnomAD v2, exomes cohort). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8122G>A has been reported in the literature in multiple compound heterozygous individuals affected with classic- and variant Ataxia-Telangiectasia (A-T) (e.g., Thompson_2005, Cavalieri_2006, Reiman_2011, Jacquemin_2012, Prodosmo_2013, Claes_2013), and in heterozygous individuals affected with various tumor phenotypes, including prostate-, breast/ovarian-, and pancreatic cancer (e.g., Hata_2021, Karlsson_2021, Tavera-Tapia_2017, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased protein levels and kinase activity in an in vitro expression system (Barone_2009), and in patient derived cells (e.g. Reiman_2011, Jacquemin_2012, Prodosmo_2013, Claes_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 16941484, 23632773, 34755017, 22071889, 33436325, 23454770, 21792198, 27913932, 15928302, 29909963, 33471991). Multiple ClinVar submitters (evaluation after 2014) have cited the variant and all laboratories classified the variant as pathogenic (n = 4) or likely pathogenic (n = 8). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at