ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6203T>C (p.Leu2068Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(6); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.6203T>C (p.Leu2068Ser)
Variation ID: 489568 Accession: VCV000489568.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108317377 (GRCh38) [ NCBI UCSC ] 11: 108188104 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 19, 2018 Feb 14, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.6203T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Leu2068Ser missense NM_001330368.2:c.641-8306A>G intron variant NM_001351110.2:c.*39-8306A>G intron variant NM_001351834.2:c.6203T>C NP_001338763.1:p.Leu2068Ser missense NC_000011.10:g.108317377T>C NC_000011.9:g.108188104T>C NG_009830.1:g.99546T>C NG_054724.1:g.157456A>G LRG_135:g.99546T>C LRG_135t1:c.6203T>C LRG_135p1:p.Leu2068Ser - Protein change
- L2068S
- Other names
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- Canonical SPDI
- NC_000011.10:108317376:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ATM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10007 | 16113 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6090 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV000579619.15 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 13, 2023 | RCV000779043.17 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 13, 2023 | RCV003336057.3 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915498.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ATM c.6203T>C (p.Leu2068Ser) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two individuals … (more)
The ATM c.6203T>C (p.Leu2068Ser) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two individuals with ataxia-telangiectasia (Anheim et al. 2010; Carranza et al. 2017). Control data are unavailable for this variant. The p.Leu2068Ser variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence, the p.Leu2068Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Jun 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Accession: SCV001911475.1
First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
Comment:
The c. 6203T>C (p.Leu2068Ser) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). This missense variant … (more)
The c. 6203T>C (p.Leu2068Ser) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (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). The variant was detected in three ataxia telangiectasia probands: two compound heterozygotes with truncating variants and one homozygote (PS4_Moderate; PMID: 19440741; PMID: 27664052; PMID: 22071889). Studies in ataxia-telangiectasia patient carrier cells show trace or low levels of ATM protein, no autophosphorilation in Serine 1981 and no (or trace) phosphorylation of two substrates (H2AX Ser139 and KAP1 Ser824) upon irradiation and intermediate irradiation sensitivity in a colony survival assay (PS3_Moderate; PMID: 19440741; PMID: 27664052). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PS4_Moderate + PS3_Moderate + PP3 (PMID: 33280026). (less)
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
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Likely pathogenic
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000682313.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces leucine with serine at codon 2068 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces leucine with serine at codon 2068 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). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 19440741, 27664052). Cells derived from one of these individuals have shown decreased ATM protein expression, no detectable ATM kinase activity, and some radiosensitivity (PMID: 27664052). This variant has also been reported in the homozygous state in an individual affected with atypical ataxia-telangiectasia (PMID: 22071889, 31050087). Cells derived from this individual have shown a slight decrease in ATM protein expression and residual ATM kinase activity, suggesting that the variant is hypomorphic (PMID: 22071889, 31050087). This variant has been reported in individuals affected with breast cancer (PMID: 30303537). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. It is however important to note that this variant may be hypomorphic and the associated cancer risk may be different from that of other pathogenic ATM variants. Medical management should be considered based on the individual’s personal and family history. (less)
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Likely pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003868847.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.L2068S variant (also known as c.6203T>C), located in coding exon 42 of the ATM gene, results from a T to C substitution at nucleotide … (more)
The p.L2068S variant (also known as c.6203T>C), located in coding exon 42 of the ATM gene, results from a T to C substitution at nucleotide position 6203. The leucine at codon 2068 is replaced by serine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of ataxia telangiectasia (Anheim M et al. Neurogenetics, 2010 Feb;11:1-12; Jacquemin V et al. Eur J Hum Genet, 2012 Mar;20:305-12; Carranza D et al. Neuromolecular Med, 2017 Mar;19:161-174; Berland A et al. J Allergy Clin Immunol, 2019 Jan;143:325-334.e2). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Jul 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004043169.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 29906526, 19440741, 27664052]. … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 29906526, 19440741, 27664052]. Functional studies indicate this variant impacts protein function [PMID: 22071889, 31050087, 27664052]. (less)
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Likely pathogenic
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211971.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241019.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: ATM c.6203T>C (p.Leu2068Ser) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Four of … (more)
Variant summary: ATM c.6203T>C (p.Leu2068Ser) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251316 control chromosomes. c.6203T>C has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Anheim_2010, Carranza_2017, Jacquemin_2012) and Breast cancer (Girard_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showing an impact on protein function (Jacquemin_2012). The following publications have been ascertained in the context of this evaluation (PMID: 19440741, 27664052, 30303537, 22071889). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely pathogenic (n=4) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Jun 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001494470.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 22071889, 27664052, 31050087). 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. ClinVar contains an entry for this variant (Variation ID: 489568). This missense change has been observed in individual(s) with ataxia-telangiectasia, late-onset ataxia, or breast cancer and ataxia-telangiectasia (PMID: 19440741, 22071889, 27664052, 30303537). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2068 of the ATM protein (p.Leu2068Ser). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
Functional classification of ATM variants in ataxia-telangiectasia patients. | Fiévet A | Human mutation | 2019 | PMID: 31050087 |
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects. | Berland A | The Journal of allergy and clinical immunology | 2019 | PMID: 29906526 |
Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia. | Carranza D | Neuromolecular medicine | 2017 | PMID: 27664052 |
Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. | Jacquemin V | European journal of human genetics : EJHG | 2012 | PMID: 22071889 |
Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. | Anheim M | Neurogenetics | 2010 | PMID: 19440741 |
Text-mined citations for rs1555114558 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.