This variant causes a G>T nucleotide substitution at the +1 position of intron 60 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. 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.8786+1G>T
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.
(9)
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
9
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.8786+1G>T
Variation ID: 184741 Accession: VCV000184741.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108353881 (GRCh38) [ NCBI UCSC ] 11: 108224608 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 1, 2017 Jun 17, 2024 Feb 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.8786+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001330368.2:c.640+32039C>A intron variant NM_001351110.2:c.695-18589C>A intron variant NM_001351834.2:c.8786+1G>T splice donor NC_000011.10:g.108353881G>T NC_000011.9:g.108224608G>T NG_009830.1:g.136050G>T NG_054724.1:g.120952C>A LRG_135:g.136050G>T LRG_135t1:c.8786+1G>T - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000011.10:108353880:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- 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. |
|||
| ATM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10850 | 17460 | |
| C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6592 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 28, 2022 | RCV000164050.20 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000540315.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2022 | RCV001558979.12 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 16, 2021 | RCV002485015.8 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 29, 2024 | RCV003467284.3 |
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
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Nov 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001353288.2
First in ClinVar: Mar 25, 2020 Last updated: Jan 15, 2022 |
Comment:
This variant causes a G>T nucleotide substitution at the +1 position of intron 60 of the ATM gene. Splice site prediction tools predict that this … (more)
This variant causes a G>T nucleotide substitution at the +1 position of intron 60 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(Dec 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000214657.9
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.8786+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 59 of the ATM gene. To our knowledge, … (more)
The c.8786+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 59 of the ATM gene. To our knowledge, this alteration has not been reported in published literature to date; however, a different nucleotide change at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous ataxia-telangiectasia kindreds (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45; Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46; Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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)
|
|
|
Pathogenic
(Feb 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004212248.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Accession: SCV001911491.1
First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
Comment:
The c.8786+1G>T variant is located in the canonical donor splice site of intron 60 and it is predicted to cause the skipping of exon 60 … (more)
The c.8786+1G>T variant is located in the canonical donor splice site of intron 60 and it is predicted to cause the skipping of exon 60 and the disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). Semiquantitative splicing analysis shows a 55% of altered band and 45% of wild type band after RT-PCR of puromycin-cultured lymphocyte carrier RNA. The altered band is the result of the predicted skipping of exon 60 (PS3_Moderate; M. Santamariña and A. Vega., unpublished data). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS3_Moderate (PMID: 33280026). (less)
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
|
|
|
Likely pathogenic
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004931506.1
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)
|
|
|
Likely pathogenic
(Jul 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000792812.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Likely pathogenic
(Jul 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002778861.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(May 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001781030.3
First in ClinVar: Aug 13, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in an individual with breast cancer (Feliubadal 2021); This variant is associated with the following publications: (PMID: 28152038, 34426522, 33280026) (less)
|
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000622851.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 60 of the ATM gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 60 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 individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). ClinVar contains an entry for this variant (Variation ID: 184741). Studies have shown that disruption of this splice site results in skipping of exon 60 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
The c.8786+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 59 of the ATM gene. To our knowledge, this alteration has not been reported in published literature to date; however, a different nucleotide change at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous ataxia-telangiectasia kindreds (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45; Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46; Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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.
Comment:
The c.8786+1G>T variant is located in the canonical donor splice site of intron 60 and it is predicted to cause the skipping of exon 60 and the disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). Semiquantitative splicing analysis shows a 55% of altered band and 45% of wild type band after RT-PCR of puromycin-cultured lymphocyte carrier RNA. The altered band is the result of the predicted skipping of exon 60 (PS3_Moderate; M. Santamariña and A. Vega., unpublished data). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS3_Moderate (PMID: 33280026).
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:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in an individual with breast cancer (Feliubadal 2021); This variant is associated with the following publications: (PMID: 28152038, 34426522, 33280026)
Comment:
This sequence change affects a donor splice site in intron 60 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 individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). ClinVar contains an entry for this variant (Variation ID: 184741). Studies have shown that disruption of this splice site results in skipping of exon 60 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
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>T nucleotide substitution at the +1 position of intron 60 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The c.8786+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 59 of the ATM gene. To our knowledge, this alteration has not been reported in published literature to date; however, a different nucleotide change at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous ataxia-telangiectasia kindreds (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45; Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46; Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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.
Comment:
The c.8786+1G>T variant is located in the canonical donor splice site of intron 60 and it is predicted to cause the skipping of exon 60 and the disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). Semiquantitative splicing analysis shows a 55% of altered band and 45% of wild type band after RT-PCR of puromycin-cultured lymphocyte carrier RNA. The altered band is the result of the predicted skipping of exon 60 (PS3_Moderate; M. Santamariña and A. Vega., unpublished data). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS3_Moderate (PMID: 33280026).
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:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in an individual with breast cancer (Feliubadal 2021); This variant is associated with the following publications: (PMID: 28152038, 34426522, 33280026)
Comment:
This sequence change affects a donor splice site in intron 60 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 individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). ClinVar contains an entry for this variant (Variation ID: 184741). Studies have shown that disruption of this splice site results in skipping of exon 60 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
| Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. | Reiman A | British journal of cancer | 2011 | PMID: 21792198 |
| Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia. | Exley AR | Clinical immunology (Orlando, Fla.) | 2011 | PMID: 21459046 |
| Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry. | Graña B | Breast cancer research and treatment | 2011 | PMID: 21445571 |
| Novel mutations and defective protein kinase C activation of T-lymphocytes in ataxia telangiectasia. | García-Pérez MA | Clinical and experimental immunology | 2001 | PMID: 11298136 |
| Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. | Laake K | Human mutation | 2000 | PMID: 10980530 |
| Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. | Li A | American journal of medical genetics | 2000 | PMID: 10817650 |
| Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. | Teraoka SN | American journal of human genetics | 1999 | PMID: 10330348 |
| ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. | Stankovic T | American journal of human genetics | 1998 | PMID: 9463314 |
| A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. | Wright J | American journal of human genetics | 1996 | PMID: 8808599 |
| Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening. | Telatar M | American journal of human genetics | 1996 | PMID: 8659541 |
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Text-mined citations for rs17174393 ...
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 Nov 25, 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.