ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.3925G>A (p.Ala1309Thr)
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.3925G>A (p.Ala1309Thr)
Variation ID: 127377 Accession: VCV000127377.106
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108284405 (GRCh38) [ NCBI UCSC ] 11: 108155132 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 7, 2017 May 12, 2024 Mar 9, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000051.4:c.3925G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Ala1309Thr missense NM_001351834.2:c.3925G>A NP_001338763.1:p.Ala1309Thr missense NC_000011.10:g.108284405G>A NC_000011.9:g.108155132G>A NG_009830.1:g.66574G>A LRG_135:g.66574G>A LRG_135t1:c.3925G>A LRG_135p1:p.Ala1309Thr - Protein change
- A1309T
- Other names
- p.A1309T:GCA>ACA
- NM_000051.4(ATM):c.3925G>A
- Canonical SPDI
- NC_000011.10:108284404:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Exome Aggregation Consortium (ExAC) 0.00062
The Genome Aggregation Database (gnomAD), exomes 0.00068
Trans-Omics for Precision Medicine (TOPMed) 0.00078
The Genome Aggregation Database (gnomAD) 0.00081
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00108
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 |
10314 | 16610 |
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/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 20, 2021 | RCV000115182.22 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000122844.41 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000212006.25 | |
Benign/Likely benign (11) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2023 | RCV000587234.47 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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May 3, 2023 | RCV001249851.10 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001355352.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 11, 2023 | RCV001798315.11 | |
Benign (2) |
reviewed by expert panel
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Mar 9, 2022 | RCV001762219.12 |
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
(Mar 09, 2022)
|
reviewed by expert panel
Method: curation
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
Accession: SCV002499290.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The ATM c.3925G>A (p.Ala1309Thr) variant has a GnomAD (v2.1.1) filtering allele frequency of 0.1050% (NFE) which is above the ATM BS1 threshold of .05% (BS1). … (more)
The ATM c.3925G>A (p.Ala1309Thr) variant has a GnomAD (v2.1.1) filtering allele frequency of 0.1050% (NFE) which is above the ATM BS1 threshold of .05% (BS1). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals without ataxia-telangiectasia (Internal laboratory contributions; BP2_strong). Multiple in silico protein predictors predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. (less)
|
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Likely benign
(Jul 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805543.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
|
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Benign
(Mar 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902584.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
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Benign
(Dec 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001143106.1
First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
|
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Likely benign
(Aug 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001439180.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Comment:
The ATM c.3925G>A (p.Ala1309Thr) missense variant has a frequency of 0.0006864 (194 of 282,624 alleles) in gnomAD v2.1.1 with a maximum frequency of 0.001209 (156 … (more)
The ATM c.3925G>A (p.Ala1309Thr) missense variant has a frequency of 0.0006864 (194 of 282,624 alleles) in gnomAD v2.1.1 with a maximum frequency of 0.001209 (156 of 129,002) in the European non-Finnish subpopulation (BS1_Supporting, https://gnomad.broadinstitute.org/). The most frequent known pathogenic variants in this gene occur at maximal subpopulation frequencies of 0.05%, 0.039%, and 0.033%. Five of seven in silico tools predict a benign effect of this variant on protein function (BP4; https://pecan.stjude.cloud/variant/8471). This variant has been observed in several patients with breast cancer (PMID: 26976419, 17393301, 20305132) and Lynch syndrome (PMID: 25980754). However, case control studies indicate that the variant is observed in equal frequencies in control individuals, suggesting that the variant is not likely to be associated with disease (PMID: 30287823, 19781682, 21787400). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1_Supporting, BP4. (less)
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Benign
(Oct 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694267.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 11, 2020 |
Comment:
Variant summary: ATM c.3925G>A (p.Ala1309Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: ATM c.3925G>A (p.Ala1309Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 282624 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). In addition, in certain European subpopulations the variant was observed with an even higher occurrence, e.g. in the North-western European control population it occurred with a frequency of 0.0019, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Additionally, the variant was reported in 17/ 2559 European American women (i.e. with an allele frequency of 0.0015), who were older than age 70, and have never had cancer (in the FLOSSIES database); the allele frequency in this cohort is 1.5-fold higher than the MPAF (0.001), further supporting a benign role for the variant. The variant, c.3925G>A, has been reported in the literature in multiple individuals affected with Breast Cancer and other tumor phenotypes (without strong evidence for causality), and was also reported in controls, including a Swiss, non-cancer related cohort, where the variant was observed with an allele frequency of 0.005 (Kraemer_2019). In a large case-control study combined with meta-analysis, the variant was not associated with an increased risk for breast cancer (Tavtigian_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 15 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (7x), likely benign (5x) or benign (3x). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Jan 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000593510.2
First in ClinVar: Jan 07, 2017 Last updated: Jan 29, 2022 |
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Benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760561.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
|
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Likely benign
(Jul 11, 2023)
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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: SCV002042186.2
First in ClinVar: Dec 29, 2021 Last updated: Dec 24, 2023 |
|
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Likely benign
(May 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714398.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
BS1, BP4
Number of individuals with the variant: 52
|
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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
|
Invitae
Accession: SCV000166102.15
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024 |
|
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Likely benign
(Jul 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185953.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
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Likely benign
(Dec 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149091.12
First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018 |
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
(Dec 12, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745124.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
|
Likely benign
(Jul 20, 2021)
|
criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002536662.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
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Likely benign
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838528.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
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Benign
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602552.3
First in ClinVar: Sep 28, 2017 Last updated: Sep 30, 2023 |
Comment:
The ATM c.3925G>A; p.Ala1309Thr variant (rs149711770) is reported in the literature in individuals affected with various cancers, but without clear disease association (Broeks 2008, Dominguez-Valentin … (more)
The ATM c.3925G>A; p.Ala1309Thr variant (rs149711770) is reported in the literature in individuals affected with various cancers, but without clear disease association (Broeks 2008, Dominguez-Valentin 2018, Momozawa 2018, Xie 2018). This variant is also reported in equal numbers of cases and controls (Tavtigian 2009, Yu 2021), and in at least one family in which the variant did not segregate with disease (Wang 2019). This variant is also reported in ClinVar (Variation ID: 127377), and is found in the general population with an overall allele frequency of 0.069% (194/282624 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.076). Based on available information, this variant is considered to be benign. (less)
|
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Benign
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898528.3
First in ClinVar: Apr 25, 2019 Last updated: Dec 09, 2023 |
|
|
Likely benign
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001148417.22
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
ATM: BP4
Number of individuals with the variant: 5
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550220.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Ala1309Thr variant was identified in 15 of 138364 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in … (more)
The ATM p.Ala1309Thr variant was identified in 15 of 138364 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in 3 of 30056 control chromosomes (frequency: 0.0001) from healthy individuals (Broeks 2008, Tavtigian 2009, Balmana 2016, Bernstein 2010, Goldgar 2011, Momozawa 2018, Tung 2016, Young 2016). The variant was also identified in dbSNP (ID: rs149711770) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and five other submitters; and as uncertain significance by four submitters), and in LOVD 3.0 (3x as likely benign). The variant was identified in control databases in 191 of 276962 chromosomes at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 156 of 126510 chromosomes (freq: 0.001), African in 9 of 24028 chromosomes (freq: 0.0004), Other in 3 of 6460 chromosomes (freq: 0.0005), Latino in 6 of 34408 chromosomes (freq: 0.0002), East Asian in 15 of 18852 chromosomes (freq: 0.0008), Finnish in 2 of 25780 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish or South Asian populations. This variant was identified by our laboratory in a patient with a co-occurring pathogenic BRIP1 variant (c.133G>T, p.Glu45*), increasing the likelihood that the ATM p.Ala1309Thr variant does not have clinical significance. The p.Ala1309 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
Number of individuals with the variant: 1
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001905685.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Likely benign
(Nov 14, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745812.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001919078.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001955945.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV002036169.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Not Provided
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV002029139.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 04-03-2019 by Lab or GTR ID Division of Clinical Laboratories Kingston General Hospital. GenomeConnect assertions are reported … (more)
Variant interpreted as Uncertain significance and reported on 04-03-2019 by Lab or GTR ID Division of Clinical Laboratories Kingston General Hospital. 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:
Neoplasm of ovary (present)
Age: 30-39 years
Sex: female
Testing laboratory: Division of Clinical Laboratories Kingston General Hospital
Date variant was reported to submitter: 2019-04-03
Testing laboratory interpretation: Uncertain significance
|
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Uncertain significance
(Nov 20, 2014)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228296.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Uncertain significance
(Jan 20, 2019)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482828.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
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Uncertain significance
(Sep 29, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000787861.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
Uncertain significance
(Mar 09, 2018)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
|
Hereditary Breast and Ovarian Cancer Syndrome
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV001424013.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1309 in the ATM … (more)
This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1309 in the ATM protein. The variant is found at a frequency of 0.0062 (75/120390 alleles) in the Exome Aggregation Consortium database, with highest frequency among non-Finnish Europeans (0.00091, 61/66688 alleles). This residue (Ala1309) is not well conserved and is not found in a protein functional domain. In silico computational tools are inconclusive in their predictions on effects on protein structure and function. In a breast cancer case-control study (PMID: 19781682), the variant was found in 3/2531 cases and 3/2245 controls. These data indicate that this variant is not likely to be associated with disease, as it is found in equal frequencies in case and control populations. However, there is insufficient evidence to conclusively rule out any disease association. Thus, we consider this to be a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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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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Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort. | Kraemer D | Swiss medical weekly | 2019 | PMID: 31422574 |
Identification of Rare Variants Predisposing to Thyroid Cancer. | Wang Y | Thyroid : official journal of the American Thyroid Association | 2019 | PMID: 30957677 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. | Dominguez-Valentin M | Hereditary cancer in clinical practice | 2018 | PMID: 29371908 |
Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. | Xie Y | Clinical genetics | 2018 | PMID: 28580595 |
Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
Next generation sequencing of the nidus of early (adenosquamous proliferation rich) radial sclerosing lesions of the breast reveals evidence for a neoplastic precursor lesion. | Wilsher MJ | The journal of pathology. Clinical research | 2017 | PMID: 28451460 |
Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. | Annala M | European urology | 2017 | PMID: 28259476 |
Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service. | Hamblin A | PLoS medicine | 2017 | PMID: 28196074 |
Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease. | Marjanovic I | Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | 2016 | PMID: 27460089 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. | Nadeu F | Blood | 2016 | PMID: 26837699 |
Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Spectrum of gene mutations detected by next generation exome sequencing in brain metastases of lung adenocarcinoma. | Preusser M | European journal of cancer (Oxford, England : 1990) | 2015 | PMID: 26164066 |
Molecular characterization of patients with pathologic complete response or early failure after neoadjuvant chemotherapy for locally advanced breast cancer using next generation sequencing and nCounter assay. | Park K | Oncotarget | 2015 | PMID: 26009992 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Copy number variants in clinical next-generation sequencing data can define the relationship between simultaneous tumors in an individual patient. | Sehn JK | Experimental and molecular pathology | 2014 | PMID: 24886963 |
Molecular characterization of patient-derived human pancreatic tumor xenograft models for preclinical and translational development of cancer therapeutics. | Mattie M | Neoplasia (New York, N.Y.) | 2013 | PMID: 24204193 |
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. | Hasselblatt M | Genes, chromosomes & cancer | 2013 | PMID: 23074045 |
Rare variants in the ATM gene and risk of breast cancer. | Goldgar DE | Breast cancer research : BCR | 2011 | PMID: 21787400 |
Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. | Bernstein JL | Journal of the National Cancer Institute | 2010 | PMID: 20305132 |
Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. | Tavtigian SV | American journal of human genetics | 2009 | PMID: 19781682 |
The spectrum of ATM missense variants and their contribution to contralateral breast cancer. | Broeks A | Breast cancer research and treatment | 2008 | PMID: 17393301 |
Oligonucleotide microarrays demonstrate the highest frequency of ATM mutations in the mantle cell subtype of lymphoma. | Fang NY | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12697903 |
Positive end expiratory pressure via a portable system in thoracic dystrophy. | Edees S | Archives of disease in childhood | 1992 | PMID: 1739330 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/65d2266d-93af-405f-b678-b9b808d3bbe1 | - | - | - | - |
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Text-mined citations for rs149711770 ...
HelpRecord last updated May 12, 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.