ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.7988T>C (p.Val2663Ala)
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(6); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.7988T>C (p.Val2663Ala)
Variation ID: 133635 Accession: VCV000133635.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108333946 (GRCh38) [ NCBI UCSC ] 11: 108204673 (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 Jun 17, 2024 Feb 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.7988T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Val2663Ala missense NM_001330368.2:c.641-24875A>G intron variant NM_001351110.2:c.*38+1274A>G intron variant NM_001351834.2:c.7988T>C NP_001338763.1:p.Val2663Ala missense NC_000011.10:g.108333946T>C NC_000011.9:g.108204673T>C NG_009830.1:g.116115T>C NG_054724.1:g.140887A>G LRG_135:g.116115T>C LRG_135t1:c.7988T>C LRG_135p1:p.Val2663Ala - Protein change
- V2663A
- Other names
- p.V2663A:GTT>GCT
- NP_000042.3:p.Val2663Ala
- Canonical SPDI
- NC_000011.10:108333945:T:C
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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 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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 |
10341 | 16658 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6301 |
Conditions - Germline
Condition
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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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Uncertain significance (2) |
criteria provided, single submitter
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Sep 7, 2023 | RCV000120160.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 3, 2023 | RCV000214426.18 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV000231221.26 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2023 | RCV000656763.13 | |
Benign (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002225366.9 | |
ATM-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Sep 29, 2023 | RCV004551180.1 |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 17, 2024 | RCV003315730.9 |
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
(Jun 14, 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: SCV000209650.17
First in ClinVar: Feb 24, 2015 Last updated: Jun 24, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history with breast and … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history with breast and other cancers (Tung et al., 2016; Yehia et al., 2018; Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 29684080, 24728327, 26976419, 30171174, 26193622, 32832836) (less)
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Uncertain significance
(Sep 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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ATM-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118471.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ATM c.7988T>C variant is predicted to result in the amino acid substitution p.Val2663Ala. This variant has been reported individuals with breast cancer (Table A2, … (more)
The ATM c.7988T>C variant is predicted to result in the amino acid substitution p.Val2663Ala. This variant has been reported individuals with breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Table S2, Wilson et al. 2019. PubMed ID: 30171174), unspecified cancer types (Table S9, Yehia et al. 2018. PubMed ID: 29684080), and inflammatory bowel disease (Table S2, Kelsen et al. 2015. PubMed ID: 26193622). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108204673-T-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/133635/). 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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Likely benign
(Jan 18, 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: SCV000283068.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Uncertain significance
(Feb 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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Baylor Genetics
Accession: SCV005056977.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Likely benign
(Sep 23, 2016)
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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: SCV000911033.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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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: SCV002504772.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
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Likely benign
(Apr 03, 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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Myriad Genetics, Inc.
Accession: SCV004019737.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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 07, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916554.3
First in ClinVar: Jun 02, 2019 Last updated: Nov 04, 2023 |
Comment:
Variant summary: ATM c.7988T>C (p.Val2663Ala) 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.7988T>C (p.Val2663Ala) 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 5.6e-05 in 251198 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia Telangiectasia or Breast Cancer, allowing no conclusion about variant significance. c.7988T>C has been reported in the literature in at-least one individual affected with Breast Cancer (Tung_2016). This report does not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26976419). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; Likely benign, n=3; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 12, 2020)
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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: SCV003827474.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000278121.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.V2663A variant (also known as c.7988T>C), located in coding exon 53 of the ATM gene, results from a T to C substitution at nucleotide … (more)
The p.V2663A variant (also known as c.7988T>C), located in coding exon 53 of the ATM gene, results from a T to C substitution at nucleotide position 7988. The valine at codon 2663 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(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: SCV001462597.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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
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ITMI
Accession: SCV000084302.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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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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Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. | Matejcic M | JCO precision oncology | 2020 | PMID: 32832836 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
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 |
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 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Text-mined citations for rs377648506 ...
HelpRecord last updated Jun 17, 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.