ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6820G>A (p.Ala2274Thr)
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.
Uncertain significance(6); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.6820G>A (p.Ala2274Thr)
Variation ID: 135776 Accession: VCV000135776.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108326070 (GRCh38) [ NCBI UCSC ] 11: 108196797 (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 19, 2017 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.6820G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Ala2274Thr missense NM_001330368.2:c.641-16999C>T intron variant NM_001351110.2:c.*38+9150C>T intron variant NM_001351834.2:c.6820G>A NP_001338763.1:p.Ala2274Thr missense NC_000011.10:g.108326070G>A NC_000011.9:g.108196797G>A NG_009830.1:g.108239G>A NG_054724.1:g.148763C>T LRG_135:g.108239G>A LRG_135t1:c.6820G>A LRG_135p1:p.Ala2274Thr Q13315:p.Ala2274Thr - Protein change
- A2274T
- Other names
- p.A2274T:GCA>ACA
- Canonical SPDI
- NC_000011.10:108326069: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00012
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
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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
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 |
10314 | 16610 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6280 |
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000122880.30 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2018 | RCV000159644.18 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2023 | RCV000588200.22 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 20, 2023 | RCV001268972.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 27, 2019 | RCV001250436.9 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Oct 11, 2023 | RCV001824286.10 |
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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Uncertain significance
(Jun 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: no
Allele origin:
germline
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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001424808.1 First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020 |
Comment:
The c.6820G>A variant has been reported in individuals with breast cancer (Broeks 2008, Li 2016 ) but did not segregate with disease in two families … (more)
The c.6820G>A variant has been reported in individuals with breast cancer (Broeks 2008, Li 2016 ) but did not segregate with disease in two families with breast and ovarian cancer (Thorstenson 2003). The c.6820G>A variant has also been reported in the literature to co-occur with the ATM c.4724G>A variant in individuals with breast cancer, chronic lymphocytic leukemia (CLL) and multiple myeloma (Austen 2008, Tavtigian 2008, and Navrkalova 2012). The individual with CLL also had a somatic ATM Gln984Glu and a somatic 11q chromosomal deletion. The c.6820 variant has a combined allele frequency of 0.00009 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk. (less)
Indication for testing: family history of breast cancer, Ashkenazi Jewish ancestry
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Uncertain significance
(Dec 06, 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: SCV000209633.16
First in ClinVar: Feb 24, 2015 Last updated: Dec 17, 2022 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: most show no … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: most show no or minimal impact on protein expression, kinase activity, ability to correct the radiosensitive phenotype of A-T cell lines, and levels of radiation-induced chromosome aberrations (Stankovic et al., 1999; Scott et al., 2002; Barone et al., 2009); Observed in individuals with ATM-related and other cancers, but also in unaffected controls (Dork et al., 2001; Scott et al., 2002; Austen et al., 2008; Broeks et al., 2008; Tavtigian et al., 2009; Skowronska et al., 2011; Navrkalova et al., 2013; Li et al., 2016; Yang et al., 2016; Pearlman et al., 2017; Tiao et al., 2017; Hauke et al., 2018; Renault et al., 2018; elebi and Bolat, 2022); This variant is associated with the following publications: (PMID: 23585524, 10023947, 26787654, 16652348, 11606401, 19781682, 18573109, 21933854, 17393301, 12810666, 22529920, 15279808, 11805335, 19431188, 26534844, 27449771, 21787400, 27978560, 29665859, 28652578, 29522266, 33128190, 30613976, 23532176, elebi2022[article]) (less)
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Uncertain significance
(Jan 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002771712.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 26, 2024 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 19431188, 11805335) (less)
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Likely benign
(Jan 29, 2024)
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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: SCV000166138.12
First in ClinVar: Jun 16, 2014 Last updated: Feb 14, 2024 |
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Uncertain significance
(Feb 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000705521.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Jul 20, 2016)
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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: SCV000910700.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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Uncertain significance
(Apr 27, 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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Illumina Laboratory Services, Illumina
Accession: SCV001260750.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jul 02, 2018)
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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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Mendelics
Accession: SCV000838580.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Likely benign
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694333.4
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
Comment:
Variant summary: ATM c.6820G>A (p.Ala2274Thr) results in a non-conservative amino acid change located in the FAT domain of the encoded protein sequence. Four of five … (more)
Variant summary: ATM c.6820G>A (p.Ala2274Thr) results in a non-conservative amino acid change located in the FAT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 271674 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00011 vs 0.001), allowing no conclusion about variant significance. c.6820G>A has been reported in the literature in individuals with breast cancer (at least 5 patients), multiple myeloma (at least 1 patient) and at least 2 patients with chronic lymphocytic leukemia (example, Stankovic_1999, Dork_2001, Thorstenson_2003, Austen_2008, Broeks_2008, Tavtigian_2009, Skowronska_2011, Navrkalova_2012, Li_2016). In two reported HBOC families, this variant did not cosegregate with disease, suggesting a notion that it does not cause HBOC (Thorstenson_2003). However, the variants role as risk allele cannot be ruled out as the variant was found in a meta-analysis to be overrepresented in a patient population compared to a control population (Tavtigian_2009). These data do not allow any conclusion about variant significance. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as demonstrated by protein expression, kinase activity, and radiation-induced chromosome aberrations assays (Scott 2002, Barone 2009). The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 19431188, 17393301, 11606401, 26534844, 23585524, 27978560, 11805335, 21933854, 10023947, 19781682, 12810666, 28652578, 27449771). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=3, VUS, n=6, Pathogenic, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of actionable clinical and functional evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Sep 06, 2018)
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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: SCV000215124.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Pathogenic
(Oct 21, 2021)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Tip-toe gait
Affected status: yes
Allele origin:
unknown
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Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV002074128.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Clinical Features:
Pes cavus (present) , Clinodactyly (present) , Brachydactyly (present) , Pectus excavatum (present) , limited range of motion of the upper ankle (present)
Age: 0-9 years
Sex: male
Method: Gene panel analysis
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 in breast and brain tumors: a comprehensive review. | Estiar MA | Cancer biology & medicine | 2018 | PMID: 30197789 |
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations. | Yang XR | Human genetics | 2016 | PMID: 27449771 |
Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families. | Li J | Journal of medical genetics | 2016 | PMID: 26534844 |
ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin. | Navrkalova V | Haematologica | 2013 | PMID: 23585524 |
Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. | George Priya Doss C | PloS one | 2012 | PMID: 22529920 |
ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. | Skowronska A | Haematologica | 2012 | PMID: 21933854 |
Rare variants in the ATM gene and risk of breast cancer. | Goldgar DE | Breast cancer research : BCR | 2011 | PMID: 21787400 |
Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. | Tavtigian SV | American journal of human genetics | 2009 | PMID: 19781682 |
Modeling ATM mutant proteins from missense changes confirms retained kinase activity. | Barone G | Human mutation | 2009 | PMID: 19431188 |
Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients. | Austen B | British journal of haematology | 2008 | PMID: 18573109 |
The spectrum of ATM missense variants and their contribution to contralateral breast cancer. | Broeks A | Breast cancer research and treatment | 2008 | PMID: 17393301 |
Contributions of ATM mutations to familial breast and ovarian cancer. | Thorstenson YR | Cancer research | 2003 | PMID: 12810666 |
Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. | Scott SP | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11805335 |
Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. | Dörk T | Cancer research | 2001 | PMID: 11606401 |
Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. | Stankovic T | Lancet (London, England) | 1999 | PMID: 10023947 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
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Text-mined citations for rs567060474 ...
HelpRecord last updated May 08, 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.