ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.1A>C (p.Met1Leu)
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.1A>C (p.Met1Leu)
Variation ID: 187213 Accession: VCV000187213.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108227625 (GRCh38) [ NCBI UCSC ] 11: 108098352 (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 Mar 24, 2015 May 1, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.1A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Met1Leu missense initiator codon variant NM_001351834.2:c.1A>C NP_001338763.1:p.Met1Leu missense initiator codon variant NM_001351835.2:c.1A>C NP_001338764.1:p.Met1Leu missense initiator codon variant NM_001351836.2:c.1A>C NP_001338765.1:p.Met1Leu missense initiator codon variant NC_000011.10:g.108227625A>C NC_000011.9:g.108098352A>C NG_009830.1:g.9794A>C LRG_135:g.9794A>C LRG_135t1:c.1A>C LRG_135p1:p.Met1Leu - Protein change
- M1L
- Other names
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- Canonical SPDI
- NC_000011.10:108227624: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 |
10313 | 16609 |
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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May 22, 2023 | RCV000166918.8 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 25, 2023 | RCV000576648.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV004019993.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Jan 20, 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: SCV000678178.2
First in ClinVar: Jan 07, 2018 Last updated: Sep 03, 2023 |
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Likely pathogenic
(Oct 20, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918503.2
First in ClinVar: Jun 03, 2019 Last updated: Sep 03, 2023 |
Comment:
Variant summary: The ATM c.1A>C (p.Met1Leu) variant involves the alteration of a conserved nucleotide causing a substitution of initiation codon in exon 2 and is … (more)
Variant summary: The ATM c.1A>C (p.Met1Leu) variant involves the alteration of a conserved nucleotide causing a substitution of initiation codon in exon 2 and is located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) (InterPro). 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Since this variant affects the initiation codon, it is expected to alter the translation of ATM protein. Two other substitution variants in the initiation codon (p.Met1Ile and p.Met1Thr) have been classified as likely pathogenic/pathogenic by our laboratory. This variant is absent in 215414 control chromosomes in gnomAD. One clinical diagnostic laboratory has classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic. (less)
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV000807215.3
First in ClinVar: Jan 07, 2018 Last updated: Sep 03, 2023 |
Comment:
This start codon mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory in trans with a pathogenic … (more)
This start codon mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory in trans with a pathogenic missense mutation in a 3-year-old male with hypotonia, ataxic gait, short stature, dysmorphic features. (less)
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Pathogenic
(Dec 25, 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: SCV000941428.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is not present … (more)
This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with ataxia-telangiectasia (PMID: 9463314, 12552559, 21792198, 22649200). ClinVar contains an entry for this variant (Variation ID: 187213). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 22, 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: SCV001339383.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant results in the loss of translation initiation methionine codon 1 of the ATM protein. This variant is expected to result in an absent … (more)
This variant results in the loss of translation initiation methionine codon 1 of the ATM protein. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in trans with a pathogenic missense mutation in a child affected with hypotonia, ataxic gait, short stature, dysmorphic features (Clinvar variation ID: 187213 and SCV000807215.1) and in an individual affected with early-onset breast cancer (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different translation initiation codon loss variant (ATM c.2T>C / p.Met1?) is a well documented pathogenic variant (Clinvar variation ID: 187213). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 10, 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: SCV004933103.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. … (more)
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 9463314, 21792198, 12552559, 22649200, 22146522, 30549301]. (less)
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Pathogenic
(Jan 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: SCV000217737.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the ATM gene and results from an A to C substitution … (more)
The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the ATM gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation was identified in 1/1207 cases of BRCA1/2-negative French women diagnosed with breast cancer who had a sister with breast cancer and in 0/1199 general population controls (Girard E et al. Int J Cancer. 2019 04;144(8):1962-74). Two other disease-causing mutations at the initiation codon, c.3G>A and c.2T>C, have been reported in a compound heterozygous state in patients with Ataxia Telangectasia (AT) (Gilad S, Hum. Mol. Genet. 1996 Apr; 5(4):433-9. Buzin CH, Hum. Mutat. 2003 Feb; 21(2):123-31). Another alteration at the initiation codon, c.1A>G, has been identified in trans with an additional ATM alteration in a patient with very mild AT symptoms. Functional analysis of the two alterations independently revealed that the c.1A>G allele produced very low protein levels, and the protein that was produced was of a lower molecular weight than wild type ATM suggesting initiation at a downstream methionine resulting in a premature truncation codon (Byrd PJ, Br. J. Cancer 2012 Jan; 106(2):262-8). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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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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Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. | Schon K | Annals of neurology | 2019 | PMID: 30549301 |
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
Classical ataxia telangiectasia patients have a congenitally aged immune system with high expression of CD95. | Carney EF | Journal of immunology (Baltimore, Md. : 1950) | 2012 | PMID: 22649200 |
Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia. | Byrd PJ | British journal of cancer | 2012 | PMID: 22146522 |
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 |
Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. | Micol R | The Journal of allergy and clinical immunology | 2011 | PMID: 21665257 |
Comprehensive scanning of the ATM gene with DOVAM-S. | Buzin CH | Human mutation | 2003 | PMID: 12552559 |
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 |
Predominance of null mutations in ataxia-telangiectasia. | Gilad S | Human molecular genetics | 1996 | PMID: 8845835 |
Text-mined citations for rs730881359 ...
HelpRecord last updated May 01, 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.