ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6814G>A (p.Glu2272Lys)
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.6814G>A (p.Glu2272Lys)
Variation ID: 265315 Accession: VCV000265315.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108326064 (GRCh38) [ NCBI UCSC ] 11: 108196791 (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 26, 2017 Jun 17, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.6814G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Glu2272Lys missense NM_001330368.2:c.641-16993C>T intron variant NM_001351110.2:c.*38+9156C>T intron variant NM_001351834.2:c.6814G>A NP_001338763.1:p.Glu2272Lys missense NC_000011.10:g.108326064G>A NC_000011.9:g.108196791G>A NG_009830.1:g.108233G>A NG_054724.1:g.148769C>T LRG_135:g.108233G>A LRG_135t1:c.6814G>A LRG_135p1:p.Glu2272Lys - Protein change
- E2272K
- Other names
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- Canonical SPDI
- NC_000011.10:108326063: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.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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 |
10396 | 16718 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6304 |
Conditions - Germline
Condition
Help
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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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Oct 14, 2021 | RCV000586472.16 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV000553239.17 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2023 | RCV000565662.15 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001355550.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 29, 2024 | RCV003469196.2 | |
ATM-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Feb 16, 2023 | RCV004547648.2 |
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
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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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Uncertain significance
(Jun 20, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694332.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The ATM c.6814G>A (p.Glu2272Lys) variant involves the alteration of a conserved nucleotide. The variant is present in RAD-3 domain however it is unknown … (more)
Variant summary: The ATM c.6814G>A (p.Glu2272Lys) variant involves the alteration of a conserved nucleotide. The variant is present in RAD-3 domain however it is unknown whether the domain is critical to protein function or it involves a critical residue. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 120880 control chromosomes. The variant was found as germline variant in one acute lymphoblastic leukemia sample and as somatic variant in one esophagus sample (Gumy Pause_2003, Lin_2014); however without strong evidence for causality. Because of the absence of sufficient clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. (less)
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Uncertain significance
(Aug 08, 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: SCV000793244.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Uncertain significance
(May 12, 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: SCV000708587.2
First in ClinVar: Oct 10, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Nov 19, 2018)
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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: SCV000322063.8
First in ClinVar: Oct 10, 2016 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted ATM c.6814G>A at the cDNA level, p.Glu2272Lys (E2272K) at the protein level, and results in the change of a Glutamic Acid … (more)
This variant is denoted ATM c.6814G>A at the cDNA level, p.Glu2272Lys (E2272K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual with childhood acute lymphoblastic leukemia (Gumy Pause 2003). ATM Glu2272Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Glu2272Lys is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Glu2272Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Nov 01, 2022)
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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: SCV000622689.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2272 of the ATM protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2272 of the ATM protein (p.Glu2272Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ataxia telangiectasia and with leukemia (PMID: 12673804, 31050087). ClinVar contains an entry for this variant (Variation ID: 265315). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 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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Ambry Genetics
Accession: SCV000660521.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.E2272K variant (also known as c.6814G>A), located in coding exon 46 of the ATM gene, results from a G to A substitution at nucleotide … (more)
The p.E2272K variant (also known as c.6814G>A), located in coding exon 46 of the ATM gene, results from a G to A substitution at nucleotide position 6814. The glutamic acid at codon 2272 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic ATM mutation in an individual with an atypical Ataxia Telangiectasia phenotype (Fiévet A et al. Hum Mutat, 2019 10;40:1713-1730). It was also identified in a pediatric patient with acute lymphoblastic leukemia and a woman with early-onset breast cancer (Gumy Pause et al. Hum. Mutat. 2003 May;21(5):554; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(May 08, 2019)
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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: SCV001349026.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Uncertain significance
(May 29, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002538483.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.6814G>A (p.E2272K) variant has been reported as compound heterozygous in at least one individual with atypical ataxia telangiectasia (PMID: 31050087) and was also … (more)
The ATM c.6814G>A (p.E2272K) variant has been reported as compound heterozygous in at least one individual with atypical ataxia telangiectasia (PMID: 31050087) and was also observed in a patient with childhood acute lymphoblastic leukemia (PMID: 12673804). In vitro functional studies have shown that this variant alters the cellular localization of the ATM protein (PMID: 31050087). In silico tools that predict the impact of the variant on protein function are inconclusive. This variant was observed in 1/8710 chromosomes in the African American (AFR) population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID: 265315). Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
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Uncertain significance
(Oct 14, 2021)
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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: SCV002771727.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Feb 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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ATM-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105924.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ATM c.6814G>A variant is predicted to result in the amino acid substitution p.Glu2272Lys. This variant has been reported in an individual with acute lymphoblastic … (more)
The ATM c.6814G>A variant is predicted to result in the amino acid substitution p.Glu2272Lys. This variant has been reported in an individual with acute lymphoblastic leukemia and an individual with breast cancer (Table 2, Gumy Pause et al. 2003. PubMed ID: 12673804; Supplement, Lerner-Ellis et al. 2021. PubMed ID: 32885271). It has also been reported along with a second ATM variant in an individual with atypical ataxia-telangiectasia (Patient AT26, Table S2, Fiévet et al. 2019. PubMed ID: 31050087). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108196791-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/265315/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Mar 29, 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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Baylor Genetics
Accession: SCV004211993.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550470.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Glu2272Lys variant was identified in 1 of 114 proband chromosomes (frequency: 0.009) from individuals or families with B-precursor ALL, and was not identified … (more)
The ATM p.Glu2272Lys variant was identified in 1 of 114 proband chromosomes (frequency: 0.009) from individuals or families with B-precursor ALL, and was not identified in 128 control chromosomes from healthy individuals (Pause 2003). The variant was identified in dbSNP (ID: rs886039471) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and in LOVD 3.0 (1x as pathogenic (2019)). The variant was identified in control databases in 1 of 30966 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 8728 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, South Asian, and Finnish, populations. The p.Glu2272 residue is conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Glu2272Lys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(Jan 12, 2021)
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no assertion criteria provided
Method: clinical testing
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Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002079886.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Functional classification of ATM variants in ataxia-telangiectasia patients. | Fiévet A | Human mutation | 2019 | PMID: 31050087 |
ATM gene alterations in childhood acute lymphoblastic leukemias. | Gumy Pause F | Human mutation | 2003 | PMID: 12673804 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
Text-mined citations for rs886039471 ...
HelpRecord last updated Jun 30, 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.