ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6543G>T (p.Glu2181Asp)
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.
Uncertain significance(5); Benign(1); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.6543G>T (p.Glu2181Asp)
Variation ID: 127425 Accession: VCV000127425.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108321391 (GRCh38) [ NCBI UCSC ] 11: 108192118 (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 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.6543G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Glu2181Asp missense NM_001330368.2:c.641-12320C>A intron variant NM_001351110.2:c.*39-12320C>A intron variant NM_001351834.2:c.6543G>T NP_001338763.1:p.Glu2181Asp missense NC_000011.10:g.108321391G>T NC_000011.9:g.108192118G>T NG_009830.1:g.103560G>T NG_054724.1:g.153442C>A LRG_135:g.103560G>T LRG_135t1:c.6543G>T LRG_135p1:p.Glu2181Asp - Protein change
- E2181D
- Other names
- p.E2181D:GAG>GAT
- NP_000042.3:p.Glu2181Asp
- Canonical SPDI
- NC_000011.10:108321390:G:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00015
Exome Aggregation Consortium (ExAC) 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
The Genome Aggregation Database (gnomAD) 0.00056
Trans-Omics for Precision Medicine (TOPMed) 0.00061
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
10314 | 16610 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6280 |
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 21, 2021 | RCV000115230.20 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000196735.24 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 1, 2022 | RCV000212044.22 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 10, 2023 | RCV000587205.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002225324.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2024 | RCV003407492.5 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003492464.1 |
Submissions - Germline
Classification
Help
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
Help
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
Help
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
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002504755.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
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Likely benign
(Nov 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774765.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Feb 01, 2024)
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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: SCV000254131.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Jul 11, 2018)
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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: SCV000214314.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Oct 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070968.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694327.4
First in ClinVar: Mar 17, 2018 Last updated: May 16, 2022 |
Comment:
Variant summary: ATM c.6543G>T (p.Glu2181Asp) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. … (more)
Variant summary: ATM c.6543G>T (p.Glu2181Asp) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) 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 0.00015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing the Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was found in 8/2559 African American women (allele frequency: 0.001563) older than 70 years of age, who had no history of cancer (FLOSSIES database). c.6543G>T has also been reported in the literature in individuals affected with Breast Cancer (e.g. Bernstein 2010, Haiman_2013, Tung 2016, Adedokun_2020, George_2021, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with a pathogenic variant ATM c.3049C>T (p.Gln1017X) has been seen multiple times in our lab, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, and two as likely benign. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Apr 21, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537947.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149139.19
First in ClinVar: May 17, 2014 Last updated: May 27, 2023 |
Comment:
Observed in individuals with breast cancer (Bernstein et al., 2010; Tung et al., 2016; Yehia et al., 2018; Weitzel et al., 2019; Adedokun et al., … (more)
Observed in individuals with breast cancer (Bernstein et al., 2010; Tung et al., 2016; Yehia et al., 2018; Weitzel et al., 2019; Adedokun et al., 2020; George et al., 2021; Eygelaar et al., 2022; Guindalini et al., 2022); 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: 30413523, 26976419, 26689913, 21787400, 25182519, 20305132, 23555315, 28652578, 32098697, 31871109, 33646313, 35039564, 30447919, 23532176, 33606809, 29684080, 31206626, 35264596) (less)
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838576.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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ATM-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004107343.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The ATM c.6543G>T variant is predicted to result in the amino acid substitution p.Glu2181Asp. This variant has been previously reported in individuals with breast cancer … (more)
The ATM c.6543G>T variant is predicted to result in the amino acid substitution p.Glu2181Asp. This variant has been previously reported in individuals with breast cancer (see for example Bernstein et al. 2010. PubMed ID: 20305132, Supplementary Table 2; Tung et al. 2016. PubMed ID: 26976419; Adedokun et al. 2020. PubMed ID: 31871109) and endometrial cancer (Lu et al. 2015. PubMed ID: 26689913, Supplementary Data 12). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD, an allele frequency that is likely too high for a disease causing variant. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity, ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127425/). Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Dec 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000703945.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Jan 13, 2020)
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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: SCV000537555.4
First in ClinVar: Sep 24, 2016 Last updated: Mar 25, 2020 |
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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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Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean. | George SHL | JAMA network open | 2021 | PMID: 33646313 |
Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis. | Sandoval RL | PloS one | 2021 | PMID: 33606809 |
Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon. | Adedokun B | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 31871109 |
Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. | Weitzel JN | Cancer | 2019 | PMID: 31206626 |
Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas. | de Jonge MM | Clinical cancer research : an official journal of the American Association for Cancer Research | 2019 | PMID: 30413523 |
Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data. | van Marcke C | Critical reviews in oncology/hematology | 2018 | PMID: 30447919 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Whole exome sequence analysis of Peters anomaly. | Weh E | Human genetics | 2014 | PMID: 25182519 |
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. | Bernstein JL | Journal of the National Cancer Institute | 2010 | PMID: 20305132 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
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Text-mined citations for rs138828590 ...
HelpRecord last updated May 08, 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.