ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.331+1G>A
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.331+1G>A
Variation ID: 487450 Accession: VCV000487450.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108229324 (GRCh38) [ NCBI UCSC ] 11: 108100051 (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 Jan 7, 2018 Feb 14, 2024 Oct 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.331+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001351834.2:c.331+1G>A splice donor NM_001351835.2:c.332G>A NP_001338764.1:p.Ser111Asn missense NM_001351836.2:c.332G>A NP_001338765.1:p.Ser111Asn missense NC_000011.10:g.108229324G>A NC_000011.9:g.108100051G>A NG_009830.1:g.11493G>A LRG_135:g.11493G>A LRG_135t1:c.331+1G>A - Protein change
- S111N
- Other names
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- Canonical SPDI
- NC_000011.10:108229323: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
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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 |
10000 | 16103 |
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
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 20, 2023 | RCV000576405.7 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2022 | RCV000788912.3 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2023 | RCV000777474.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV003459414.1 |
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 21, 2016)
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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: SCV000678177.1
First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018 |
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Likely pathogenic
(Feb 05, 2019)
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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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Blueprint Genetics
Accession: SCV000928204.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(Dec 19, 2022)
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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: SCV001181314.4
First in ClinVar: Mar 16, 2020 Last updated: Apr 15, 2023 |
Comment:
The c.331+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the ATM gene. This nucleotide position is … (more)
The c.331+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. 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). Another mutation at this donor site, c.331+5G>A, results in the same abnormal splicing event and has been reported in multiple individuals with a clinical diagnosis of ataxia-telangiectasia (A-T) (Nakamura K, et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Morio T, et al. Int. J. Hematol. 2009 Nov; 90(4):455-62, Verhagen MM et al, Neurology 2009 Aug; 73(6):430-7, Verhagen MM, et al. Hum. Mutat. 2012 Mar; 33(3):561-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Aug 20, 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: SCV000828879.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 4 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 4 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 clinical features of ataxia-telangiectasia (PMID: 31921190). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 487450). Studies have shown that disruption of this splice site results in skipping of exon 4 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)
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Likely pathogenic
(Mar 15, 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: SCV000913336.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the canonical +1 position of intron 4 of the ATM gene. Splice site prediction tools … (more)
This variant causes a G to A nucleotide substitution at the canonical +1 position of intron 4 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been observed in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 31921190). This variant has also been reported in an individual affected with gastroesophageal junction adenocarcinoma, cervical cancer and parathyroid cancer (PMID: 35078243). 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)
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Pathogenic
(Oct 17, 2022)
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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: SCV002584161.2
First in ClinVar: Oct 22, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in … (more)
Not observed in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with pancreatic cancer (Hutchings et al., 2019); This variant is associated with the following publications: (PMID: 31285527, 31921190) (less)
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Pathogenic
(Oct 02, 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: SCV004207084.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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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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ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications. | El Jabbour T | Journal of the National Cancer Institute | 2022 | PMID: 35078243 |
Ataxia Telangiectasia Diagnosed on Newborn Screening-Case Cohort of 5 Years' Experience. | Mandola AB | Frontiers in immunology | 2019 | PMID: 31921190 |
Text-mined citations for rs1555055356 ...
HelpRecord last updated Feb 20, 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.