ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.1339C>T (p.Arg447Ter)
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.1339C>T (p.Arg447Ter)
Variation ID: 127337 Accession: VCV000127337.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108250804 (GRCh38) [ NCBI UCSC ] 11: 108121531 (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 29, 2015 May 1, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.1339C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Arg447Ter nonsense NM_001351834.2:c.1339C>T NP_001338763.1:p.Arg447Ter nonsense NC_000011.10:g.108250804C>T NC_000011.9:g.108121531C>T NG_009830.1:g.32973C>T LRG_135:g.32973C>T LRG_135t1:c.1339C>T LRG_135p1:p.Arg447Ter - Protein change
- R447*
- Other names
- p.R447*:CGA>TGA
- Canonical SPDI
- NC_000011.10:108250803:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
10313 | 16609 |
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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2023 | RCV000115141.16 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2024 | RCV000169409.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 8, 2018 | RCV001258117.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2023 | RCV000211960.7 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162534.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV003460799.2 |
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
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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Pathogenic
(Dec 05, 2016)
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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: SCV000694179.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The ATM c.1339C>T (p.Arg447X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense … (more)
Variant summary: The ATM c.1339C>T (p.Arg447X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3049C>T/p.Gln1017X, c.4396C>T/p.Arg1466X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121264 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported as germline variant in mutliple Ataxia-Telangiectasia patients in autosomal recessive inheritance and patients with ovarian cancer, chronic lymphocyti leukemia or prostate cancer in autosomal dominant inheritance. It also has been reported in at least one patient with aggressive cutaneous squamous cell carcinoma as a somatic variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 13, 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: SCV002530287.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.1339C>T (p.R447X) variant has been reported in heterozygosity in at least 3 with ataxia-telangiectasia (PMIDs: 8845835, 15164409, 30772474), and at least 5 individuals … (more)
The ATM c.1339C>T (p.R447X) variant has been reported in heterozygosity in at least 3 with ataxia-telangiectasia (PMIDs: 8845835, 15164409, 30772474), and at least 5 individuals with breast cancer, ovarian cancer, and prostate cancer (PMIDs 27433846, 26681312, 28779002, 30322717, 31948886), among reports of additional individuals with ataxia-telangiectasia and cancer. This variant is a founder variant in the Druze population (PMID: 15164409, 8845835). This nonsense variant creates a premature stop codon at residue 447 of the ATM protein. This variant was observed in 1/16256 chromosomes in the African/African American population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 127337). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573174.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000127337 / PMID: 8845835). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present) , Frequent falls (present)
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Likely pathogenic
(Oct 17, 2014)
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criteria provided, single submitter
Method: literature only
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Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220813.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Feb 01, 2023)
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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: SCV000149050.16
First in ClinVar: May 17, 2014 Last updated: Feb 18, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed with a pathogenic variant on the opposite allele (in trans) in individuals with ataxia telangiectasia in published literature (Gilad et al., 1996; Fares et al., 2004; Perez-Villena et al., 2013; Hoche et al., 2014; Kraus et al., 2014); Observed in individuals with breast, prostate, and other cancers (Pritchard et al., 2016; Susswein et al., 2016; Barbalho et al., 2021); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27433846, 15164409, 25037873, 26681312, 32522261, 29922827, 35047863, 25525159, 8845835, 23612382, 24763289, 24568663, 26778106, 24789685, 28152038, 28779002, 30322717, 31447099, 31589614, 32427313, 35260754, 35441217, 35586824, 29625052, 30130155, 25303977, 35155181, 36140756, 30772474, 31948886) (less)
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Pathogenic
(Oct 09, 2023)
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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: SCV004207036.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 27, 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: SCV000537674.4
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 10 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 10 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with autosomal recessive ataxia-telangiectasia, with several individuals confirmed to be homozygotes or compound heterozygotes with a second pathogenic variant in trans (PMID: 8845835, 15164409, 23612382, 24789685, 25037873), indicating that this variant contributes to disease. This variant has also been reported in individuals affected with breast cancer, ovarian cancer, prostate cancer, and/or underwent hereditary cancer multigene panel testing (PMID: 28779002, 24763289, 26681312, 27433846, 33471991). This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(May 21, 2021)
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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: SCV000172928.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R447* pathogenic mutation (also known as c.1339C>T), located in coding exon 9 of the ATM gene, results from a C to T substitution at … (more)
The p.R447* pathogenic mutation (also known as c.1339C>T), located in coding exon 9 of the ATM gene, results from a C to T substitution at nucleotide position 1339. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in several individuals with classic ataxia-telangiectasia including three Druze families, suggesting it is a founder mutation in the Druze population (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Fares F et al. Prenat. Diagn. 2004 May;24:358-62). It has also been reported in individuals with breast, ovarian, or prostate cancer (Susswein LR et al. Genet. Med., 2016 08;18:823-32; Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53; Decker B et al. J. Med. Genet., 2017 Nov;54:732-741). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Oct 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Susceptibility to breast cancer
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434990.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.1339C>T (p.Arg447*) variant in the ATM gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA … (more)
The c.1339C>T (p.Arg447*) variant in the ATM gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has an extremely low frequency in large databases of genetic variation in the general population. Mono-allelic variants in the ATM gene have been associated with susceptibility to breast cancer (MIM #114480) whereas bi-allelic variants in this gene are associated with Ataxia-telangiectasia (MIM #208900). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 8845835, 15164409) and in patients affected with cancer (PMID: 26681312, 27433846). Therefore, the c.1339C>T (p.Arg447*) variant in the ATM gene is classified as pathogenic. (less)
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Pathogenic
(Mar 16, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502232.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Feb 17, 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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Revvity Omics, Revvity
Accession: SCV003811079.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 03, 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: SCV000622246.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg447*) in the ATM gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg447*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs587779815, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and ovarian and prostate cancer (PMID: 8845835, 15164409, 23612382, 24789685, 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 127337). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 16, 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: SCV004931864.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Oct 29, 2020)
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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: SCV002090956.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758212.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607155.1
First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (present)
Age: 20-29 years
Sex: female
Testing laboratory: Color Genomics, Inc.
Date variant was reported to submitter: 2016-05-02
Testing laboratory interpretation: Pathogenic
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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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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. | Palmer JR | Journal of the National Cancer Institute | 2020 | PMID: 32427313 |
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
ATM mutation spectrum in Russian children with ataxia-telangiectasia. | Suspitsin E | European journal of medical genetics | 2020 | PMID: 30772474 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
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 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. | Pritchard CC | The New England journal of medicine | 2016 | PMID: 27433846 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Ten new ATM alterations in Polish patients with ataxia-telangiectasia. | Podralska MJ | Molecular genetics & genomic medicine | 2014 | PMID: 25614872 |
Mutational landscape of aggressive cutaneous squamous cell carcinoma. | Pickering CR | Clinical cancer research : an official journal of the American Association for Cancer Research | 2014 | PMID: 25303977 |
Cognitive phenotype in ataxia-telangiectasia. | Hoche F | Pediatric neurology | 2014 | PMID: 25037873 |
Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. | Kraus M | Journal of clinical immunology | 2014 | PMID: 24789685 |
Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. | LaDuca H | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24763289 |
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. | Huang Y | Neuromolecular medicine | 2013 | PMID: 23807571 |
Ataxia-telangiectasia and wilms tumor: reduced treatment but early relapse. | Pérez-Villena A | Journal of pediatric hematology/oncology | 2013 | PMID: 23612382 |
Identification of two mutations for ataxia telangiectasia among the Druze community. | Fares F | Prenatal diagnosis | 2004 | PMID: 15164409 |
Predominance of null mutations in ataxia-telangiectasia. | Gilad S | Human molecular genetics | 1996 | PMID: 8845835 |
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Text-mined citations for rs587779815 ...
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.