ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6503C>T (p.Ser2168Leu)
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(9); Benign(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.6503C>T (p.Ser2168Leu)
Variation ID: 220531 Accession: VCV000220531.46
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108321351 (GRCh38) [ NCBI UCSC ] 11: 108192078 (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 Apr 29, 2017 Oct 8, 2024 Sep 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000051.4:c.6503C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Ser2168Leu missense NM_001330368.2:c.641-12280G>A intron variant NM_001351110.2:c.*39-12280G>A intron variant NM_001351834.2:c.6503C>T NP_001338763.1:p.Ser2168Leu missense NC_000011.10:g.108321351C>T NC_000011.9:g.108192078C>T NG_009830.1:g.103520C>T NG_054724.1:g.153482G>A LRG_135:g.103520C>T LRG_135t1:c.6503C>T LRG_135p1:p.Ser2168Leu - Protein change
- S2168L
- Other names
- -
- Canonical SPDI
- NC_000011.10:108321350: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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 30, 2024 | RCV000206774.28 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 27, 2024 | RCV000216900.21 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2024 | RCV000588892.16 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763709.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jun 2, 2021 | RCV001268980.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 14, 2023 | RCV004567472.1 |
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
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894589.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Uncertain significance
(Jun 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694325.3
First in ClinVar: Mar 17, 2018 Last updated: Jun 22, 2021 |
Comment:
Variant summary: ATM c.6503C>T (p.Ser2168Leu) results in a non-conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Three of … (more)
Variant summary: ATM c.6503C>T (p.Ser2168Leu) results in a non-conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 299890 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The frequency in the East Asian subpopulation is close to, but does not exceed, the estimated maximum allele frequency expected for a pathogenic variant in ATM causing Breast Cancer (0.00082 vs 0.001), allowing no conclusion about variant significance. c.6503C>T has been reported in the literature in individuals affected with Breast and Prostate Cancers (e.g.Haiman_2013, Xie_2018, Fostira_2018, Momozawa_2018, Wei_2019, Kwong_2020). In one large case-control study within the Japanese population, this variant was found in both cases and controls and was not shown to be associated with breast cancer (OR=0.4, p=0.222; Momozawa_2018) . These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5682C>G, p.Y1894X; Wei_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
Uncertain significance
(Mar 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Department of Neurology, Xijing Hospital, Fourth Military Medical University
Accession: SCV002553227.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
|
|
Uncertain significance
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838574.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
Uncertain significance
(May 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774773.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(May 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537533.7
First in ClinVar: May 29, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with leucine at codon 2168 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces serine with leucine at codon 2168 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 23555315, 28580595, 28779002, 29335925, 30287823, 33471991) and in unaffected individuals (PMID: 30287823, 32658311, 33471991). This variant has also been identified in 24/282838 chromosomes 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)
|
|
Likely benign
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000261140.12
First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024 |
|
|
Uncertain significance
(Jul 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000274735.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.S2168L variant (also known as c.6503C>T), located in coding exon 44 of the ATM gene, results from a C to T substitution at nucleotide … (more)
The p.S2168L variant (also known as c.6503C>T), located in coding exon 44 of the ATM gene, results from a C to T substitution at nucleotide position 6503. The serine at codon 2168 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in numerous cancer cohorts as well as unaffected control groups across studies (Decker B et al. J. Med. Genet. 2017;54(11):732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). Additionally, 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). It has also been identified in individuals diagnosed with breast cancer (Haiman CA et al. PLoS Genet, 2013 Mar;9:e1003419; Fostira F et al. Breast Cancer Res. Treat. 2018;169(1):105-113; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Kwong A et al. J Mol Diagn, 2020 Apr;22:544-554). This alteration has also been reported in conjunction with an ATM frameshift mutation in a patient with unexplained ataxia; phase was not reported (Cheng HL et al. Transl Neurodegener, 2021 Oct;10:40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Sep 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568996.8
First in ClinVar: Apr 29, 2017 Last updated: Oct 08, 2024 |
Comment:
Observed with a truncating ATM variant in a child with ataxia and dysarthria, and it is not known whether the variants occurred on the same … (more)
Observed with a truncating ATM variant in a child with ataxia and dysarthria, and it is not known whether the variants occurred on the same (in cis) allele or on opposite (in trans) alleles (PMID: 34663476); Observed in individuals with breast, pancreatic or colon cancer, and also in unaffected controls in studies of various cancer types (PMID: 36243179, 23555315, 28779002, 29335925, 30287823, 29684080, 32068069, 32980694, 32658311, 28580595); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31248605, 29684080, 32068069, 32658311, 28580595, 23555315, 28779002, 29335925, 30287823, 36300887, 32980694, 36243179, 34663476, 31214711, 35218119, 38845987, 23532176) (less)
|
|
Benign
(Feb 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005045427.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
|
|
Uncertain significance
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005057147.1
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: SCV001457419.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias. | Cheng HL | Translational neurodegeneration | 2021 | PMID: 34663476 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel. | Kwong A | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32068069 |
Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls. | Momozawa Y | Journal of the National Cancer Institute | 2020 | PMID: 31214711 |
Germline DNA Repair Gene Mutation Landscape in Chinese Prostate Cancer Patients. | Wei Y | European urology | 2019 | PMID: 31248605 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
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 |
Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer. | Fostira F | Breast cancer research and treatment | 2018 | PMID: 29335925 |
Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. | Xie Y | Clinical genetics | 2018 | PMID: 28580595 |
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
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 |
click to load more click to collapse |
Text-mined citations for rs200431631 ...
HelpRecord 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.