ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.5497-2A>C
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.5497-2A>C
Variation ID: 449345 Accession: VCV000449345.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108304673 (GRCh38) [ NCBI UCSC ] 11: 108175400 (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 Dec 19, 2017 May 1, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.5497-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001351834.2:c.5497-2A>C splice acceptor NC_000011.10:g.108304673A>C NC_000011.9:g.108175400A>C NG_009830.1:g.86842A>C LRG_135:g.86842A>C LRG_135t1:c.5497-2A>C - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:108304672:A: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 |
10314 | 16610 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000521216.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000563654.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 29, 2023 | RCV000557758.13 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV001171404.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003483650.1 |
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
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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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Likely pathogenic
(Dec 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000796308.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447234.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Breast carcinoma (present)
Sex: female
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Pathogenic
(Dec 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580538.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4, PM3, PM2_SUP
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Number of individuals with the variant: 2
Sex: male
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Likely pathogenic
(Sep 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002584677.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Comment:
The ATM c.5497-2A>C intronic change results from a A to C substitution at the -2 position of intron 36 of the ATM gene. RNA studies … (more)
The ATM c.5497-2A>C intronic change results from a A to C substitution at the -2 position of intron 36 of the ATM gene. RNA studies have shown that this variant causes abnormal splicing which results in frameshift and premature protein truncation (PMID: 10330348, internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org) and is not reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). This variant has been observed in the heterozygous state in an individual with ataxia-telangiectasia, however a second variant was not identified (PMID: 10330348). In summary, this variant meets criteria to be classified as likely pathogenic. (less)
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Pathogenic
(Jun 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027696.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Criteria applied: PVS1,PS3_mod, PS4_mod, PM2_sup
Clinical Features:
Family history of cancer (present)
Sex: female
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Pathogenic
(Oct 03, 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: SCV000617369.2
First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023 |
Comment:
Canonical splice site variant demonstrated to result in a null allele through the use of cryptic splice site leading to premature stop codon in a … (more)
Canonical splice site variant demonstrated to result in a null allele through the use of cryptic splice site leading to premature stop codon in a gene for which loss of function is a known mechanism of disease (Teraoka et al., 1999; Casadei et al., 2019); Observed in individuals with early onset breast cancer and other cancers (Renault et al., 2018; Casadei et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS38-2A>C; This variant is associated with the following publications: (PMID: 31589614, 34687117, 26837699, 25525159, 30303537, 31843900, 10330348, 29665859) (less)
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Pathogenic
(Mar 25, 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: SCV004212044.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: curation
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Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV004228282.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Found compound heterozygous in AT patient. According to the ACMG standard criteria we chose these criteria: PVS1 (very strong pathogenic): ClinGen Interpretation Guidelines for ATM … (more)
Found compound heterozygous in AT patient. According to the ACMG standard criteria we chose these criteria: PVS1 (very strong pathogenic): ClinGen Interpretation Guidelines for ATM Version 1.1: PVS1_very strong [experimental data for NMD (list A)] The c.5497-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the ATM gene, PS3 (strong pathogenic): RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec, Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31, and Ambry Genetics internal data)., PM2 (supporting pathogenic): ClinGen Interpretation Guidelines for ATM Version 1.1: PM2_supporting [absent/rare from controls] (less)
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Pathogenic
(Apr 11, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000687623.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant (also known as IVS38-2A>C in the literature) causes an A to C nucleotide substitution at the -2 position of intron 36 of the … (more)
This variant (also known as IVS38-2A>C in the literature) causes an A to C nucleotide substitution at the -2 position of intron 36 of the ATM gene. RNA studies have shown that this variant causes the deletion of the first 61 nucleotides of exon 37 in the RNA transcript, creating a frameshift and premature translation stop signal (PMID: 10330348, 14695534, 31843900). The aberrant RNA transcript is expected to result in an absent or disrupted protein product. This variant has been reported in the homozygous state or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 10330348, 14695534, 21665257). This variant has also been reported in an individual affected with breast cancer (PMID: 32125938). This variant has not been identified 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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Pathogenic
(Dec 29, 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: SCV000622595.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 36 of the ATM gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 36 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348). This variant is also known as IVS38-2A>C. ClinVar contains an entry for this variant (Variation ID: 449345). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10330348, 31843900; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 25, 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: SCV004933144.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
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Pathogenic
(Jun 29, 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: SCV000660446.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.5497-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the ATM gene. This mutation … (more)
The c.5497-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the ATM gene. This mutation (designated as IVS38-2A>C) was reported in an individual diagnosed with ataxia-telangiectasia (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31; Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 01, 2019)
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no assertion criteria provided
Method: research
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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King Laboratory, University of Washington
Accession: SCV001251308.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Comment:
Transcript analysis by cBROCA
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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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Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer. | Yadav S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2020 | PMID: 32125938 |
Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. | Micol R | The Journal of allergy and clinical immunology | 2011 | PMID: 21665257 |
Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene: maximum entropy estimates of splice junction strengths. | Eng L | Human mutation | 2004 | PMID: 14695534 |
Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. | Teraoka SN | American journal of human genetics | 1999 | PMID: 10330348 |
Text-mined citations for rs786203796 ...
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.