This variant causes a G to A nucleotide substitution at the -1 position of intron 27 of the ATM gene. Functional RNA studies have shown that this variant (described as IVS29-1G>A) disrupts a canonical splice site and activates a cryptic splice site one nucleotide downstream, resulting in a frameshift and premature stop codon (PMID: 14695534). This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 14695534). 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 Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.4110-1G>A
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.4110-1G>A
Variation ID: 407707 Accession: VCV000407707.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108288976 (GRCh38) [ NCBI UCSC ] 11: 108159703 (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 26, 2017 May 1, 2024 Jan 23, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.4110-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001351834.2:c.4110-1G>A splice acceptor NC_000011.10:g.108288976G>A NC_000011.9:g.108159703G>A NG_009830.1:g.71145G>A LRG_135:g.71145G>A LRG_135t1:c.4110-1G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000011.10:108288975:G:A
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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
Help
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
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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 |
10839 | 17439 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 25, 2023 | RCV000462992.14 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2022 | RCV000566126.9 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 23, 2024 | RCV001310115.4 |
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
Help
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499657.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Pathogenic
(Sep 13, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002528996.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.4110-1G>A variant has been reported in at least one individual with ataxia telangiectasia (PMID: 14695534). It was not observed in the large and … (more)
The ATM c.4110-1G>A variant has been reported in at least one individual with ataxia telangiectasia (PMID: 14695534). It was not observed in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 407707). In silico tools predict that the variant disrupts the original splice acceptor site in intron 27 and activates a cryptic splice site one nucleotide downstream. These predictions have been confirmed by an experimental study (PMID: 14695534). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Pathogenic
(Dec 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004212151.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Likely pathogenic
(Jan 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001341159.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 27 of the ATM gene. Functional RNA studies have shown … (more)
This variant causes a G to A nucleotide substitution at the -1 position of intron 27 of the ATM gene. Functional RNA studies have shown that this variant (described as IVS29-1G>A) disrupts a canonical splice site and activates a cryptic splice site one nucleotide downstream, resulting in a frameshift and premature stop codon (PMID: 14695534). This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 14695534). 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 Likely Pathogenic. (less)
|
|
|
Pathogenic
(Apr 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000547109.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in altered splicing and introduces … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). ClinVar contains an entry for this variant (Variation ID: 407707). This variant is also known as IVS29-1G>A. Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 14695534). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 27 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. (less)
|
|
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Likely pathogenic
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004931319.1
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)
|
|
|
Pathogenic
(Nov 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000667952.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.4110-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 27 of the ATM gene. This alteration … (more)
The c.4110-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 27 of the ATM gene. This alteration (designated as IVS29-1G>A) was previously detected in a Hispanic individual diagnosed with ataxia-telangiectasia and was shown to disrupt the native acceptor splice site, resulting in a new splice site and deletion of the first nucleotide of the next coding exon which leads to a frameshift (Eng L et al. Hum Mutat. 2004 Jan;23:67-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). ClinVar contains an entry for this variant (Variation ID: 407707). This variant is also known as IVS29-1G>A. Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 14695534). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 27 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.
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 an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
The c.4110-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 27 of the ATM gene. This alteration (designated as IVS29-1G>A) was previously detected in a Hispanic individual diagnosed with ataxia-telangiectasia and was shown to disrupt the native acceptor splice site, resulting in a new splice site and deletion of the first nucleotide of the next coding exon which leads to a frameshift (Eng L et al. Hum Mutat. 2004 Jan;23:67-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 27 of the ATM gene. Functional RNA studies have shown that this variant (described as IVS29-1G>A) disrupts a canonical splice site and activates a cryptic splice site one nucleotide downstream, resulting in a frameshift and premature stop codon (PMID: 14695534). This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 14695534). 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 Likely Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). ClinVar contains an entry for this variant (Variation ID: 407707). This variant is also known as IVS29-1G>A. Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 14695534). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 27 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.
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 an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
The c.4110-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 27 of the ATM gene. This alteration (designated as IVS29-1G>A) was previously detected in a Hispanic individual diagnosed with ataxia-telangiectasia and was shown to disrupt the native acceptor splice site, resulting in a new splice site and deletion of the first nucleotide of the next coding exon which leads to a frameshift (Eng L et al. Hum Mutat. 2004 Jan;23:67-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
Text-mined citations for rs1060501692 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.