ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.8786+1G>A
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.8786+1G>A
Variation ID: 127463 Accession: VCV000127463.51
- 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 Mar 29, 2015 Jan 25, 2025 Jan 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000051.4:c.8786+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001330368.2:c.640+32039C>T intron variant NM_001351110.2:c.695-18589C>T intron variant NM_001351834.2:c.8786+1G>A splice donor NC_000011.10:g.108353881G>A NC_000011.9:g.108224608G>A NG_009830.1:g.136050G>A NG_054724.1:g.120952C>T LRG_135:g.136050G>A LRG_135t1:c.8786+1G>A - Protein change
- -
- Other names
-
IVS60+1G>A
- Canonical SPDI
- NC_000011.10:108353880:G:A
-
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
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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 |
10997 | 17706 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6691 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000115269.23 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000169303.31 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2023 | RCV000220586.21 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 29, 2024 | RCV000763226.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 13, 2017 | RCV000761159.10 | |
Pathogenic (3) |
reviewed by expert panel
|
Jan 25, 2024 | RCV003467035.4 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jan 25, 2024)
|
reviewed by expert panel
Method: curation
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004565385.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, … (more)
The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a premature stop codon and nonsense mediated decay. The highest minor allele frequency in gnomAD v2.1.1 is 0.00003517 (4/113738) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 26896183, 10817650, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong) (less)
|
|
Pathogenic
(Feb 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant Glioma
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000891075.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
|
|
Likely pathogenic
(Aug 22, 2014)
|
criteria provided, single submitter
Method: literature only
|
Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220622.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(May 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149178.15
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stankovic 1998, Garcia-Perez 2001, Reiman 2011); Observed in the … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stankovic 1998, Garcia-Perez 2001, Reiman 2011); Observed in the heterozygous state in individuals with a personal or family history including lymphoma and colorectal cancer (Sutton 2015, AlDubayan 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS62+1G>A; This variant is associated with the following publications: (PMID: 8789452, 21445571, 25480502, 10330348, 9463314, 9443866, 10817650, 12552559, 11298136, 10980530, 8808599, 21792198, 8659541, 27479817, 29478780, 30338439, 30549301, 21459046, 25525159, 29625052, 31285527, 33436325, 30612635, 26681312, 31948886, 32853339, 26896183) (less)
|
|
Pathogenic
(Jan 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020664.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000283091.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 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 present in population databases (rs17174393, gnomAD 0.002%). 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). This variant is also known as IVS62+1G>A and c.8672del115. ClinVar contains an entry for this variant (Variation ID: 127463). Studies have shown that disruption of this splice site results in skipping of exon 60 and/or activation of a cryptic splice site 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)
|
|
Pathogenic
(Aug 08, 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: SCV000682516.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the +1 position of intron 60 of the ATM gene. RNA studies have shown that … (more)
This variant causes a G to A nucleotide substitution at the +1 position of intron 60 of the ATM gene. RNA studies have shown that this variant causes the skipping of exon 60 (also known as exon 62 in the literature) or the inclusion of the first 14 nucleotides of intron 60 in the RNA transcripts (PMID: 9463314, 10330348, 10980530, 11298136). Both aberrant transcripts are expected to create a frameshift and premature truncation and result in an absent or non-functional protein product. This variant (also known as IVS62+1G>A in the literature) has been reported in many individuals affected with ataxia telangiectasia (PMID: 9463314, 10330348, 10817650, 10980530, 11298136, 12552559, 21792198). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 2/53461 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991). This variant has also been identified in 4/251450 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)
|
|
Pathogenic
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004210174.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Nov 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805632.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
|
Pathogenic
(Dec 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918527.2
First in ClinVar: May 31, 2019 Last updated: Jan 08, 2022 |
Comment:
Variant summary: ATM c.8786+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: ATM c.8786+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. Multiple publications, Laake_2000 and Stankovic_1998, functionally assessed the variant and found it to affect mRNA splicing. The variant was observed with an allele frequency of 1.2e-05 in 246218 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.2e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.8786+1G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Laake_2000, Stankovic_1998). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002527965.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.8786+1G>A variant has been reported in several individuals with ataxia telangiectasia (PMID: 30549301, 10980530, 11298136, 10330348). Additionally, has also been reported in individuals … (more)
The ATM c.8786+1G>A variant has been reported in several individuals with ataxia telangiectasia (PMID: 30549301, 10980530, 11298136, 10330348). Additionally, has also been reported in individuals with breast cancer and colorectal cancer (PMID: 26681312, 29478780, 33471991). Functional studies demonstrated the variant to result in aberrant splicing leading to absent or non-functional protein (PMID: 11298136, 10330348). It was observed in 4/113738 chromosomes of the Non-Finnish European subpopulation 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 127463). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
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: SCV004931333.1
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
(Jan 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273800.9
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.8786+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after intron 59 of the ATM gene. This alteration has been … (more)
The c.8786+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after intron 59 of the ATM gene. This alteration has been detected in numerous individuals with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Schon K et al. Ann. Neurol. 2019 02;85(2):170-180). In addition, western blot analysis has shown that this alteration results in a truncated ATM protein product (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31). 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). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024616.2
First in ClinVar: Aug 19, 2023 Last updated: Aug 04, 2024 |
|
|
Pathogenic
(Feb 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Ataxia-telangiectasia syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893858.3
First in ClinVar: Mar 31, 2019 Last updated: Jan 25, 2025 |
|
|
Pathogenic
(Oct 27, 2016)
|
no assertion criteria provided
Method: literature only
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000328305.1
First in ClinVar: Nov 06, 2016 Last updated: Nov 06, 2016 |
Geographic origin: United Kingdom
|
|
Pathogenic
(Jan 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002082758.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Ataxia-Telangiectasia. | Adam MP | - | 2023 | PMID: 20301790 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. | Schon K | Annals of neurology | 2019 | PMID: 30549301 |
Inherited DNA-Repair Defects in Colorectal Cancer. | AlDubayan SH | American journal of human genetics | 2018 | PMID: 29478780 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
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 |
Comprehensive scanning of the ATM gene with DOVAM-S. | Buzin CH | Human mutation | 2003 | PMID: 12552559 |
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 |
Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. | Lakin ND | Oncogene | 1996 | PMID: 9000145 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c0af412b-1446-4897-b7a3-43d57fec76fc | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs17174393 ...
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.