ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.7004C>T (p.Thr2335Ile)
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.
Uncertain significance(7); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.7004C>T (p.Thr2335Ile)
Variation ID: 186867 Accession: VCV000186867.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108327673 (GRCh38) [ NCBI UCSC ] 11: 108198400 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Oct 8, 2024 Aug 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.7004C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Thr2335Ile missense NM_001330368.2:c.641-18602G>A intron variant NM_001351110.2:c.*38+7547G>A intron variant NM_001351834.2:c.7004C>T NP_001338763.1:p.Thr2335Ile missense NC_000011.10:g.108327673C>T NC_000011.9:g.108198400C>T NG_009830.1:g.109842C>T NG_054724.1:g.147160G>A LRG_135:g.109842C>T LRG_135t1:c.7004C>T LRG_135p1:p.Thr2335Ile - Protein change
- T2335I
- Other names
- -
- Canonical SPDI
- NC_000011.10:108327672: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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00021
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00029
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00094
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 |
10833 | 17429 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6578 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Sep 12, 2021 | RCV000166521.19 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000168468.28 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2024 | RCV000586878.18 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 30, 2024 | RCV000855628.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 12, 2024 | RCV003468785.3 | |
not provided (1) |
no classification provided
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- | RCV003483545.1 | |
ATM-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jun 27, 2024 | RCV004739536.1 |
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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Uncertain significance
(Apr 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000790698.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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Likely benign
(Mar 17, 2020)
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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: SCV000903897.2
First in ClinVar: May 20, 2019 Last updated: Mar 25, 2020 |
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Uncertain significance
(Nov 07, 2019)
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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: SCV002067105.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222081.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00072 (18/24956 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.00072 (18/24956 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26787654 (2016) and 23555315 (2013)), pancreatic cancer (PMID: 35047863 (2022)), and hematological malignancies (PMID: 33850299 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Jun 30, 2020)
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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: SCV000217321.7
First in ClinVar: Mar 24, 2015 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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Uncertain significance
(Mar 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206248.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Apr 30, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694341.6
First in ClinVar: Mar 17, 2018 Last updated: Jul 15, 2024 |
Comment:
Variant summary: ATM c.7004C>T (p.Thr2335Ile) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. … (more)
Variant summary: ATM c.7004C>T (p.Thr2335Ile) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 4.6e-05 in 1613966 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.6e-05 vs 0.001), allowing no conclusion about variant significance. c.7004C>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast/prostate cancer and/or therapy related myeloid neoplasms (e.g. Young_2015, Haiman_2013, Singhal_2021), while it has also been reported in a pancreatic cancer case (Yu_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23555315, 33850299, 26787654, 35047863). ClinVar contains an entry for this variant (Variation ID: 186867). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Jun 12, 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: SCV005084824.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(Sep 12, 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: SCV002536897.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.7004C>T (p.T2335I) variant has been reported in individuals with breast cancer and therapy related myeloid neoplasm, undergoing hereditary cancer testing (PMID: 26787654, 33850299, … (more)
The ATM c.7004C>T (p.T2335I) variant has been reported in individuals with breast cancer and therapy related myeloid neoplasm, undergoing hereditary cancer testing (PMID: 26787654, 33850299, 23555315). This variant was observed in 18/24956 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 186867). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Likely benign
(Jan 29, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219168.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
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Uncertain significance
(Aug 14, 2024)
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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: SCV000292479.17
First in ClinVar: Jul 24, 2016 Last updated: Sep 16, 2024 |
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, hematological malignancy, or pancreatic cancer (PMID: … (more)
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, hematological malignancy, or pancreatic cancer (PMID: 33850299, 23555315, 35047863); This variant is associated with the following publications: (PMID: 26787654, 25530832, 33850299, 23555315, 35047863, 23532176) (less)
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Uncertain significance
(Sep 16, 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: SCV001458458.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(Jun 27, 2024)
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no assertion criteria provided
Method: clinical testing
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ATM-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005349501.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ATM c.7004C>T variant is predicted to result in the amino acid substitution p.Thr2335Ile. This variant has been previously reported in individuals with breast cancer, … (more)
The ATM c.7004C>T variant is predicted to result in the amino acid substitution p.Thr2335Ile. This variant has been previously reported in individuals with breast cancer, prostate cancer, pancreatic cancer, hematological malignancy, and non-small cell lung cancer (Haiman et al. 2013. PubMed ID: 23555315, Table S6.2; Sosonkina et al. 2014. PubMed ID: 25530832, Table S4; Young et al. 2016. PubMed ID: 26787654, Table S1; Singhal et al. 2021. PubMed ID: 33850299, Table S5; Yu et al. 2022. PubMed ID: 35047863). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186867). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary cancer-predisposing syndrome
Ataxia-telangiectasia syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228648.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 12-18-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 12-18-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal curvature of … (more)
Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal curvature of the vertebral column (present) (less)
Indication for testing: Presymptomatic, Family Testing
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-12-18
Testing laboratory interpretation: Uncertain significance
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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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A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk. | Yu Y | HGG advances | 2021 | PMID: 35047863 |
Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer. | Singhal D | Leukemia | 2021 | PMID: 33850299 |
Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
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 |
Text-mined citations for rs3092831 ...
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.