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Here you can see the gene and the variant being analyzed.

We summarize a large amount of clinical data on this gene here. Links are added where available to source information.

Prediction information is summarized here, the percentage shows the likelihood that the variant is pathogenic.

Agreement is a measure (out of 5 stars) of how much our predictors agree between each other. When predictors agree, the prediction is more likely to be correct.

Data quality is a measure (out of 5 stars) of how good the underlying data for this prediction is. This is an assessment of the depth of our alignments and the number of structures available, among other factors.

This table shows literature for this exact position and protein, if it is available.

This table shows literature for this position in homologous proteins, if it is available.

This is a description of our prediction.

This plot illustrates the agreement between different classifiers. If the prediction distributions align on one side it indicates increased certainty in the prediction.

This describes the data quality for this position.

Here are the four factors that contributed most to the prediction. Factors that contributed to a benign prediction are colored blue, pathogenic factors are colored red.

This plot shows all the factors for prediction. Factors that contributed to a benign prediction are colored blue, pathogenic factors are colored red.

This plot shows the conservation on this position.

Here the conservation statistics are described.

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This is a list of interactions we found for this position.

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Summary

ATM - ENST00000278616

Gene ATM - ENSG00000149311 | ENSP00000278616 | ENST00000278616
Ensembl | RefSeq | UniProt
Location GRCh38 11:108222832-108369099 Ensembl UCSC
Description ATM serine/threonine kinase

Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. {ECO:0000269|PubMed:10973490, ECO:0000269|PubMed:12556884, ECO:0000269|PubMed:14871926, ECO:0000269|PubMed:15916964, ECO:0000269|PubMed:16086026, ECO:0000269|PubMed:16858402, ECO:0000269|PubMed:17923702, ECO:0000269|PubMed:19431188, ECO:0000269|PubMed:19965871}.;

Condition(s)
  • Ataxia telangiectasia (AT)

    A rare recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. Patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation.
    The disease is caused by mutations affecting the gene represented in this entry. OMIM

    MedGen: C1458155 C0677776 C0017636 C0004135 C0950123 OrphaNet: 145 100 360 180250
PDB and PDB position 5np1 ~> 1128 (Explore)
gnomAD Exome Allele Frequency: 0.00173773
Genome Allele Frequency: 0.005922435
gnomAD
Pathogenicity benign according to VKGL
Literature for His201Tyr in HDAC8 2 papers were found describing relevant variants in this protein (Explore)
Literature for similar variants in homologous proteins Not present

Literature

Literature for Gln1128Arg in ATM

Literature available for this variant:

OBJECTIVE: To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders. METHODS: A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed. RESULTS: In comparison with typical A-T cases, our patients demonstrated later mean age at onset (6.1 vs 2.5 years, p < 0.0001), later loss of walking ability (p = 0.003), and longer survival (p = 0.0039). The presenting feature was ataxia in 71% and dysarthria and dystonia in 14% each. All patients displayed movement disorders, among which dystonia and subcortical myoclonus were the most common (86%), followed by tremor (43%). Video-oculographic recordings revealed mostly dysmetric saccades and 46% of patients had normal latencies (i.e., no oculomotor apraxia) and velocities. The α-fetoprotein (AFP) level was normal in 7%, chromosomal instability was found in 29% (vs 100% of typical patients, p = 0.0006), and immunoglobulin deficiency was found in 29% (vs 69%, p = 0.057). All patients exhibited 2 ATM mutations, including at least 1 missense mutation in 79% of them (vs 36%, p = 0.0067). CONCLUSION: There is great variability of phenotype and severity in A-T, including a wide spectrum of movement disorders. Karyotype and repeated AFP level assessments should be performed in adults with unexplained movement disorders as valuable clues towards the diagnosis. In case of a compatible phenotype, A-T should be considered even if age at onset is late and progression is slow.
PURPOSE: To identify sequence variants of the ataxia telangiectasia mutated (ATM) gene and establish their prevalence rate among American Indian (AI) as compared with non-AI cancer patients. MATERIALS AND METHODS: DNA was isolated from blood samples collected from 100 AI and 100 non-AI cancer patients undergoing radiation therapy, and a blinded assessment of the ATM sequence was conducted. Quantitative PCR assessment of copy number for each exon was also performed. The main outcome measure was the prevalence of ATM variants in the two patient populations. RESULTS: No statistically significant differences for total prevalence of ATM variants among AI and non-AI patients were found. Of the 25 variants identified, 5 variants had a prevalence of >2%, of which 4 occurred at a rate of >5% in one or both groups. The prevalence of these four variants could meaningfully be compared between the two groups. The only statistically significant difference among the groups was the c.4138C > T variant which is predicted not to affect protein function, seen in 8% of AI versus 0% of non-AI patients (P = 0.007). No exonic copy number changes were found in these patients. CONCLUSION: This study is the first to determine the prevalence of ATM variants in AIs.
Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T.
Given that there are millions of single-nucleotide polymorphisms (SNPs) in the entire human genome, a major difficulty faced by scientists in planning costly population-based genotyping is to choose target SNPs that are most likely to affect phenotypic functions and ultimately contribute to disease development. Although it is widely accepted that sequences with important functionality tend to be less variable across species because of selective pressure, to what extent evolutionary conservation is mirrored by epidemiological outcome has never been demonstrated. In this study, we surveyed odds ratios detected for 46 SNPs in 39 different cancer-related genes from 166 molecular epidemiological studies. The conservation levels of amino acid that these SNPs affected were calculated as a tolerance index by comparing sequences from different species. Our results provide evidence of a significant relationship between the detected odds ratios associated with cancer risk and the conservation levels of the SNP-affected amino acids (P = 0.002; R(2) = 0.06). Tolerance indices were further calculated for 355 nonsynonymous SNPs identified in 90 human DNA repair genes, of which 103 caused amino acid changes in very conserved positions. Our findings support the concept that SNPs altering the conserved amino acids are more likely to be associated with cancer susceptibility. Using such a molecular evolutionary approach may hold great promise for prioritizing SNPs to be genotyped in future molecular epidemiological studies.
Deficiencies in tasks of detecting and repairing DNA damage lead to mutations and chromosomal abnormalities, a hallmark of cancer. The gene mutated in ataxia-telangiectasia (A-T), ATM, is a proximal component in performing such tasks. Studies of A-T families have suggested an increased risk of breast cancer among obligate female heterozygous carriers of ATM mutations. Paradoxically, studies of sporadic and familial breast cancer have failed to demonstrate an elevated prevalence of mutations among breast cancer cases. We characterized the prevalence and distribution of 20 ATM missense mutations/polymorphisms in a population-based case-control study of 854 African-American, Latina, Japanese, and Caucasian women aged >/==" BORDER="0">45 years participating in the Multiethnic Cohort Study. The study population included 428 incident breast cancer cases and 426 controls. The prevalence of variants ranged from 0% to 13.6% among controls and varied by ethnicity (0-32.5%). Overall, these data provide little support for an association of ATM missense mutations with breast cancer among older women. We observed only one sequence variation (L546V), common among African-American women, to be overrepresented among all high-stage breast cancer cases (odds ratio, 3.35; 95% confidence interval, 1.27-8.84). After correction for multiple comparisons, this observed risk modification did not attain statistical significance. The distribution of ATM missense mutations and polymorphisms varied widely across the four ethnic groups studied. Although a single missense variant (L546V) appeared to act as a modest predictor of risk, the remaining variants were no more common in breast cancer cases as compared with controls.
BACKGROUND: Women who are heterozygous for variants in the ataxia telangiectasia mutated (ATM) gene, ATM carriers, have been reported to be at increased risk for breast cancer compared with women who do not posses an alteration in this gene. Aside from BRCA1 and BRCA2, there are few data on breast cancer susceptibility genes in African-American women. The goal of this study was to determine whether there is evidence that ATM is a breast cancer susceptibility gene in African-American women. METHODS: One hundred thirty two African-American women were screened for ATM sequence alterations. Thirty-seven (28%) were women with a histological diagnosis of breast cancer (cases). These women were not selected on the basis of a breast cancer family history. Ninety-five (72%) were age-matched women who had not been diagnosed with breast cancer (controls). Genetic variants were identified using denaturing high performance liquid chromatography (DHPLC). RESULTS: Twenty-three of the 37 (62%) cases possessed at least one ATM variant. Fifty-eight of the 95 (61%) (P = 0.54) age-matched controls harbored at least one ATM variant. For subjects specifically possessing missense variants, 46% of cases and 48% of controls had these types of sequence variants. In addition, 19% of cases and 34% of controls possessed multiple ATM sequence variants (P = 0.07). The most common polymorphisms were the 378 T --> A which was seen in 19% of cases and 27% of controls (P = 0.22), 5557 G --> A identified in 22% of cases and 18% of controls (p = 0.40), 2685 A --> G which was detected in 11% of cases and 6% of controls (P = 0.22), and 1254 A --> G which was found in 3% of cases and 9% of controls (P = 0.36). Hence, there were no significant differences in any of the genetic variants detected between the case and control subjects. CONCLUSION: We found no statistically significant differences in the overall frequency of ATM variants, nor any specific variant type or group, between African-American women who had been diagnosed with breast cancer compared with an age-matched cohort of African-American women who did not have breast cancer. ATM, therefore, does not appear to represent a breast cancer susceptibility gene in the general African-American population.

Literature for similar variants in homologous proteins

There is no literature available for variants in a homologous proteins

corona.ai classification

Classification: benign according to VKGL

This variant was found in the VKGL dataset. According to this authoritative source this variant is classified as benign. A prediction is available for this variant, but this source takes precedence in our classification.

corona.ai prediction details

Prediction: benign 15%

The Gln1128Arg mutation in the protein has been classified as benign by our ensemble classifier system, with very high confidence. There is a 92% agreement between all subclassifiers.

Data quality

Data quality for this region is considered unknown. No assessment of data quality has been made for this region.

Prediction factors

External models have estimated which sets of features contributed primarily to the classification. These sets of features are listed here.

Primary contributing factors

  • Alignment depth features point towards pathogenic
  • Structural features point towards benign
  • Alignment diversity points towards benign
  • Protein evolutionary pressure points towards benign

Evolutionary pressure

Conservation

The wildtype was observed in 80.00% of the 170 sequences analyzed. The variant type was observed in < 1% of observed sequences.


This residue is involved in 3 Hydrophobic interactions.

Interaction statistics were calculated using advanced molecular optimization techniques and may not be visible in the plain PDB file. Please download the YASARA scene to explore the interactions in more detail.