ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs)
Variation ID: 189140 Accession: VCV000189140.39
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 11q22.3 11: 108365105-108365108 (GRCh38) [ NCBI UCSC ] 11: 108235832-108235835 (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 Mar 29, 2015 Jun 17, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.8876_8879del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Asp2959fs frameshift NM_000051.3:c.8876_8879delACTG NP_000042.3:p.Asp2959Glyfs frameshift NM_001330368.2:c.640+20812_640+20815del intron variant NM_001351110.2:c.694+20812_694+20815del intron variant NM_001351834.2:c.8876_8879del NP_001338763.1:p.Asp2959fs frameshift NC_000011.10:g.108365107_108365110del NC_000011.9:g.108235834_108235837del NG_009830.1:g.147276_147279del NG_054724.1:g.109725_109728del LRG_135:g.147276_147279del LRG_135t1:c.8876_8879del - Protein change
- D2959fs
- Other names
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- Canonical SPDI
- NC_000011.10:108365104:TGACTG:TG
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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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- Links
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 |
10997 | 17706 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6691 |
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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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000169561.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2023 | RCV000236349.12 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2023 | RCV000494628.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 25, 2019 | RCV002283463.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV003468847.3 |
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
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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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Pathogenic
(Nov 07, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363786.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ATM c.8876_8879delACTG (p.Asp2959GlyfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ATM c.8876_8879delACTG (p.Asp2959GlyfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251380 control chromosomes (gnomAD). c.8876_8879delACTG has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (Carranza_2017, Mitui_2003). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate the variant to cause absence of ATM protein expression and to confer intermediate radiosensitivity (Carranza_2017). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 15, 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: SCV000903724.3
First in ClinVar: May 20, 2019 Last updated: Jan 15, 2022 |
Comment:
This variant deletes 4 nucleotides in exon 62 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 4 nucleotides in exon 62 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 3/251380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Jan 21, 2015)
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criteria provided, single submitter
Method: literature only
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Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000221056.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 04, 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: SCV000293443.11
First in ClinVar: Jul 24, 2016 Last updated: Jul 01, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.8874_8877delTGAC and c.8875_8878delGACT; This variant is associated with the following publications: (PMID: 28888541, 25479140, 31206626, 29922827, 23807571, 25614872, 36414972, 33280026, 12815592, 27664052) (less)
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Pathogenic
(Dec 14, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000283096.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asp2959Glyfs*3) in the ATM gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asp2959Glyfs*3) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs770704493, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 12815592, 27664052). This variant is also known as 8875_8878delGACT and 8874_8877delTGAC. ClinVar contains an entry for this variant (Variation ID: 189140). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 14, 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: SCV000581454.7
First in ClinVar: Jul 02, 2017 Last updated: May 01, 2024 |
Comment:
The c.8876_8879delACTG pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8876 to … (more)
The c.8876_8879delACTG pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8876 to 8879, causing a translational frameshift with a predicted alternate stop codon (p.D2959Gfs*3). This mutation has been previously identified in three individuals with ataxia telangiectasia, two of whom carried a second truncating ATM mutation (Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Of note, this alteration is also designated as 8874_8877delTGAC and 8875_8878delGACT in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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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: SCV001911492.1
First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
Comment:
The c.8876_8879del (p.Asp2959Glyfs*3) frameshift variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense … (more)
The c.8876_8879del (p.Asp2959Glyfs*3) frameshift variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0013%, (3/236,852 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0058%, (2/34,246 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with the likely pathogenic ATM variant c.8977C>T in an ataxia-telangiectasia proband and in homozygosis in another, which awards 1.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3; PMID: 12815592, 27664052). Lymphoblastoid cell lines of the homozygous patient showed no ATM protein expression and intermediate radiosensitivity (PS3_Supporting; PMID: 27664052). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3 + PS3_Supporting (PMID: 33280026). (less)
Observation 1:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast and Ovarian Cancer Susceptibility
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 2:
Clinical Features:
Breast carcinoma (present) , Ovarian cancer (present)
Indication for testing: Breast and Ovarian Cancer Susceptibility
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous pathogenic variant in BRCA2
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
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Pathogenic
(Nov 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Ataxia-telangiectasia syndrome (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV002571100.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
This variant has been previously reported as pathogenic [PMID 12815592]. Defects in ATM are the cause of ataxia telangiectasia (AT) [MIM:208900], an autosomal recessive disorder … (more)
This variant has been previously reported as pathogenic [PMID 12815592]. Defects in ATM are the cause of ataxia telangiectasia (AT) [MIM:208900], an autosomal recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. Patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation. (less)
Clinical Features:
Medulloblastoma (present) , Mild hearing impairment (present)
Age: 0-9 years
Sex: male
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Pathogenic
(Jun 23, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002022377.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 06, 2024)
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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: SCV004931937.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Dec 27, 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: SCV004209497.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Mar 05, 2021)
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no assertion criteria provided
Method: clinical testing
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Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002085047.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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 |
Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia. | Carranza D | Neuromolecular medicine | 2017 | PMID: 27664052 |
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. | Grant RC | Gastroenterology | 2015 | PMID: 25479140 |
Ten new ATM alterations in Polish patients with ataxia-telangiectasia. | Podralska MJ | Molecular genetics & genomic medicine | 2014 | PMID: 25614872 |
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. | Huang Y | Neuromolecular medicine | 2013 | PMID: 23807571 |
Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate. | Mitui M | Human mutation | 2003 | PMID: 12815592 |
Text-mined citations for rs786204726 ...
HelpRecord last updated Feb 08, 2025
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.