This missense variant replaces serine with leucine at codon 2283 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu)
Variation ID: 233915 Accession: VCV000233915.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108326098 (GRCh38) [ NCBI UCSC ] 11: 108196825 (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 Dec 19, 2017 Jun 17, 2024 Mar 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.6848C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Ser2283Leu missense NM_001330368.2:c.641-17027G>A intron variant NM_001351110.2:c.*38+9122G>A intron variant NM_001351834.2:c.6848C>T NP_001338763.1:p.Ser2283Leu missense NC_000011.10:g.108326098C>T NC_000011.9:g.108196825C>T NG_009830.1:g.108267C>T NG_054724.1:g.148735G>A LRG_135:g.108267C>T LRG_135t1:c.6848C>T LRG_135p1:p.Ser2283Leu - Protein change
- S2283L
- Other names
- -
- Canonical SPDI
- NC_000011.10:108326097:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ATM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10839 | 17439 | |
| C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6582 |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2024 | RCV000220834.18 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 31, 2022 | RCV000559536.19 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 6, 2019 | RCV001589160.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 25, 2024 | RCV004567663.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000904845.2
First in ClinVar: May 20, 2019 Last updated: Jun 22, 2020 |
Comment:
This missense variant replaces serine with leucine at codon 2283 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with leucine at codon 2283 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838581.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Uncertain significance
(Aug 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000622692.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2283 of the ATM protein (p.Ser2283Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2283 of the ATM protein (p.Ser2283Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary cancer (PMID: 33280026). ClinVar contains an entry for this variant (Variation ID: 233915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000278383.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.S2283L variant (also known as c.6848C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide … (more)
The p.S2283L variant (also known as c.6848C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6848. The serine at codon 2283 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in a patient with ovarian cancer and a patient with sebaceous adenoma in a cohort of 766 ATM variant carriers and classified as a variant of uncertain significance (Feliubadaló L et al. Clin Chem, 2021 Mar;67:518-533). This variant was also present in 1 of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not 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)
|
|
|
Uncertain significance
(Jun 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001815517.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28481359) (less)
|
|
|
Uncertain significance
(Jun 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Accession: SCV001911478.1
First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
Comment:
The c.6848C>T (p.Ser2283Leu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted … (more)
The c.6848C>T (p.Ser2283Leu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + BP4 (PMID: 33280026). (less)
Observation 1:
Clinical Features:
Ovarian serous tumor (present)
Indication for testing: Familial ovarian cancer
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 2:
Clinical Features:
Keratoacanthoma (present)
Indication for testing: Hereditary nonpolyposis colon cancer
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous pathogenic variant in MSH2
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
|
|
|
Uncertain significance
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005055825.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458455.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2283 of the ATM protein (p.Ser2283Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary cancer (PMID: 33280026). ClinVar contains an entry for this variant (Variation ID: 233915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.S2283L variant (also known as c.6848C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6848. The serine at codon 2283 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in a patient with ovarian cancer and a patient with sebaceous adenoma in a cohort of 766 ATM variant carriers and classified as a variant of uncertain significance (Feliubadaló L et al. Clin Chem, 2021 Mar;67:518-533). This variant was also present in 1 of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not 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.
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28481359)
Comment:
The c.6848C>T (p.Ser2283Leu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + BP4 (PMID: 33280026).
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. |
Comment:
This missense variant replaces serine with leucine at codon 2283 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2283 of the ATM protein (p.Ser2283Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary cancer (PMID: 33280026). ClinVar contains an entry for this variant (Variation ID: 233915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.S2283L variant (also known as c.6848C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6848. The serine at codon 2283 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in a patient with ovarian cancer and a patient with sebaceous adenoma in a cohort of 766 ATM variant carriers and classified as a variant of uncertain significance (Feliubadaló L et al. Clin Chem, 2021 Mar;67:518-533). This variant was also present in 1 of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not 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.
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28481359)
Comment:
The c.6848C>T (p.Ser2283Leu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + BP4 (PMID: 33280026).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
| A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
Text-mined citations for rs876660730 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.