ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.4258C>T (p.Leu1420Phe)
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
-
NM_000051.4(ATM):c.4258C>T (p.Leu1420Phe)
Variation ID: 128456 Accession: VCV000128456.51
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108289623 (GRCh38) [ NCBI UCSC ] 11: 108160350 (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 Jun 9, 2014 Aug 4, 2024 Jul 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000051.4:c.4258C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Leu1420Phe missense NM_001351834.2:c.4258C>T NP_001338763.1:p.Leu1420Phe missense NC_000011.10:g.108289623C>T NC_000011.9:g.108160350C>T NG_009830.1:g.71792C>T LRG_135:g.71792C>T LRG_135t1:c.4258C>T LRG_135p1:p.Leu1420Phe Q13315:p.Leu1420Phe - Protein change
- L1420F
- Other names
- p.L1420F:CTT>TTT
- NP_000042.3:p.Leu1420Phe
- Canonical SPDI
- NC_000011.10:108289622:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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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0.00619 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00619
1000 Genomes Project 30x 0.00671
Trans-Omics for Precision Medicine (TOPMed) 0.01077
The Genome Aggregation Database (gnomAD), exomes 0.01104
The Genome Aggregation Database (gnomAD) 0.01150
Exome Aggregation Consortium (ExAC) 0.01271
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01302
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
Help
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 |
10833 | 17429 |
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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Benign (11) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000116425.37 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000119139.32 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2022 | RCV000130979.23 | |
Benign (1) |
no assertion criteria provided
|
- | RCV001357258.10 | |
Benign (2) |
criteria provided, single submitter
|
Oct 23, 2023 | RCV001795159.15 | |
Benign (1) |
criteria provided, single submitter
|
Apr 19, 2022 | RCV002225336.9 | |
Benign (1) |
criteria provided, single submitter
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May 7, 2019 | RCV001798368.10 | |
Benign (1) |
criteria provided, single submitter
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May 17, 2024 | RCV004589582.1 |
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
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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Benign
(Jul 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000257605.2
First in ClinVar: Jul 06, 2014 Last updated: Jul 06, 2014 |
|
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Benign
(Feb 03, 2016)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Vantari Genetics
Accession: SCV000266991.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
|
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Benign
(Oct 15, 2013)
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criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000167089.11
First in ClinVar: Jun 23, 2014 Last updated: Dec 06, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
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Likely benign
(May 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000803143.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Benign
(Jun 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000332306.4
First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
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Likely benign
(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
|
Illumina Laboratory Services, Illumina
Accession: SCV001263901.1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(May 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042204.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
|
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Benign
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002504712.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Number of individuals with the variant: 2
Geographic origin: South Africa
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Benign
(Feb 01, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000153854.13
First in ClinVar: Jun 09, 2014 Last updated: Feb 20, 2024 |
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Benign
(Oct 23, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602559.6
First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024 |
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Benign
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002549989.6
First in ClinVar: Jul 30, 2022 Last updated: Aug 04, 2024 |
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Benign
(-)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000301668.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
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Benign
(Nov 24, 2014)
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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
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537361.1
First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017 |
|
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Likely benign
(Oct 09, 2014)
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criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743727.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Benign
(Jan 05, 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: SCV000185896.6
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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Benign
(May 17, 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: SCV005083974.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more)
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
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Benign
(Oct 05, 2015)
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no assertion criteria provided
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745813.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Benign
(-)
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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: SCV001552677.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Leu1420Phe variant was identified in 81 of 4298 proband chromosomes (frequency: 0.02) from English, French, Dutch, American Indian/Non-Indian, Australian and North American individuals … (more)
The ATM p.Leu1420Phe variant was identified in 81 of 4298 proband chromosomes (frequency: 0.02) from English, French, Dutch, American Indian/Non-Indian, Australian and North American individuals or families with familial and primary breast cancers, AT disease, CML, and individuals undergoing radiation therapy and was present in 108 of 6302 control chromosomes (frequency: 0.02) from healthy individuals (Johnson 2007 , LaPaglia 2010, Broeks 2008, Melo 2001, Petereit 2013, Renwick 2006, Li 2000, Thompson 2005, ). In 2 population-based, case-control studies, the variant was found not to increase breast cancer risk (Einarsdottir 2006, Thompson 2005). The variant was also identified in dbSNP (ID: rs1800058) as “other”, ClinVar (classified as conflicting interpretations of pathogenicity: classified benign by GeneDx, Div of Genomic Diagnostics, Children's Hospital of Philadelphia, Vantari Genetics, Prevention Genetics, Emory Genetics, Color Genomics Inc., Invitae; likely benign by Genetic Services Laboratory, U of Chicago; uncertain significance by Ambry Genetics; and unclassified by ITMI), Clinvitae (5X), LOVD 3.0 (2X), ATM-LOVD (1x). The variant was not identified in GeneInsight-COGR, Cosmic and MutDB. The variant was identified in control databases in 3069 (22 homozygous) of 272226 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 2316 of 124884 chromosomes (freq: 0.019), European (Finnish) in 279 of 25640 chromosomes (freq: 0.011), Other in 67 of 6316 chromosomes (freq: 0.011). The p.Leu1420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. (less)
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951036.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965739.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036844.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
AllHighlyPenetrant
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000150350.2
First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014 |
Comment:
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more)
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
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Benign
(Feb 20, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000787864.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905884.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923488.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084277.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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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Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls. | Fletcher O | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2010 | PMID: 20826828 |
Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study. | Einarsdóttir K | Breast cancer research : BCR | 2006 | PMID: 17132159 |
Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. | Li A | American journal of medical genetics | 2000 | PMID: 10817650 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=11&from=108160350&to=108160350 | - | - | - | - |
Text-mined citations for rs1800058 ...
HelpRecord last updated Oct 13, 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.