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.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.2281A>T (p.Thr761Ser)
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.
(10)
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.
Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(4)
Uncertain significance(4); Likely benign(4)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.2281A>T (p.Thr761Ser)
Variation ID: 135744 Accession: VCV000135744.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108257511 (GRCh38) [ NCBI UCSC ] 11: 108128238 (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 Mar 17, 2018 Oct 8, 2024 Sep 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.2281A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Thr761Ser missense NM_001351834.2:c.2281A>T NP_001338763.1:p.Thr761Ser missense NC_000011.10:g.108257511A>T NC_000011.9:g.108128238A>T NG_009830.1:g.39680A>T LRG_135:g.39680A>T LRG_135t1:c.2281A>T LRG_135p1:p.Thr761Ser Q13315:p.Thr761Ser - Protein change
- T761S
- Other names
-
p.T761S:ACT>TCT
- Canonical SPDI
- NC_000011.10:108257510:A:T
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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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00022
Trans-Omics for Precision Medicine (TOPMed) 0.00030
- 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 |
10858 | 17468 | |
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. |
|---|---|---|---|---|
| Likely benign (2) |
criteria provided, single submitter
|
Jan 28, 2024 | RCV000122833.17 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 23, 2024 | RCV000129351.20 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 17, 2024 | RCV000586568.6 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 28, 2024 | RCV002223130.5 | |
| Likely benign (1) |
criteria provided, single submitter
|
May 8, 2024 | RCV004589597.1 | |
|
ATM-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Feb 15, 2024 | RCV004551196.2 |
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
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516942.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Uncertain significance
(Nov 19, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529831.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.2281A>T (p.T761S) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 20305132). It was observed in 18/24968 … (more)
The ATM c.2281A>T (p.T761S) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 20305132). It was observed in 18/24968 chromosomes of the African/African American subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 135744). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
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Likely benign
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166091.12
First in ClinVar: Jun 16, 2014 Last updated: Feb 14, 2024 |
|
|
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Likely benign
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184115.10
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
(May 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV005083880.1
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
(Jun 28, 2024)
|
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: SCV000694215.4
First in ClinVar: Mar 17, 2018 Last updated: Sep 16, 2024 |
Comment:
Variant summary: ATM c.2281A>T (p.Thr761Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: ATM c.2281A>T (p.Thr761Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251418 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2281A>T has been reported in the literature in individuals affected with breast cancer and in individuals undertaking colorectal or prostate cancer panel testing, as well as in healthy controls (example, Giri_2022, Pearlman_2021, Einarsdottir_2005, Tavtigian_2009, Bernstein_2010, Weitzel_2019, Purrington_2020). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or other ATM-related disorders. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 22529920, 17132159, 35666082, 34250417, 19781682, 11443540, 31206626, 32868316). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 135744). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
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Uncertain significance
(Sep 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209699.18
First in ClinVar: Feb 24, 2015 Last updated: Oct 08, 2024 |
Comment:
Observed in individuals with breast, thyroid, colorectal, prostate, and/or endometrial cancer (PMID: 20305132, 29684080, 31206626, 34250417, 35666082); In silico analysis indicates that this missense variant … (more)
Observed in individuals with breast, thyroid, colorectal, prostate, and/or endometrial cancer (PMID: 20305132, 29684080, 31206626, 34250417, 35666082); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22529920, 19781682, 11443540, 20305132, 29684080, 31206626, 17132159, 34250417, 35666082) (less)
|
|
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Likely benign
(Aug 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000911210.3
First in ClinVar: May 20, 2019 Last updated: Jun 19, 2021 |
|
|
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Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462061.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Uncertain significance
(Feb 15, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ATM-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004723810.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The ATM c.2281A>T variant is predicted to result in the amino acid substitution p.Thr761Ser. This variant has been reported in patients with breast cancer (Table … (more)
The ATM c.2281A>T variant is predicted to result in the amino acid substitution p.Thr761Ser. This variant has been reported in patients with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626) as well as in controls without cancer (Thorstenson et al. 2001. PubMed ID 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has also been reported in a study of patients with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD and is has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135744/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
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 variants in this gene [PMID: 25085752].
Comment:
Variant summary: ATM c.2281A>T (p.Thr761Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251418 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2281A>T has been reported in the literature in individuals affected with breast cancer and in individuals undertaking colorectal or prostate cancer panel testing, as well as in healthy controls (example, Giri_2022, Pearlman_2021, Einarsdottir_2005, Tavtigian_2009, Bernstein_2010, Weitzel_2019, Purrington_2020). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or other ATM-related disorders. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 22529920, 17132159, 35666082, 34250417, 19781682, 11443540, 31206626, 32868316). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 135744). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Observed in individuals with breast, thyroid, colorectal, prostate, and/or endometrial cancer (PMID: 20305132, 29684080, 31206626, 34250417, 35666082); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22529920, 19781682, 11443540, 20305132, 29684080, 31206626, 17132159, 34250417, 35666082)
Comment:
The ATM c.2281A>T variant is predicted to result in the amino acid substitution p.Thr761Ser. This variant has been reported in patients with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626) as well as in controls without cancer (Thorstenson et al. 2001. PubMed ID 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has also been reported in a study of patients with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD and is has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135744/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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 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.
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 variants in this gene [PMID: 25085752].
Comment:
Variant summary: ATM c.2281A>T (p.Thr761Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251418 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2281A>T has been reported in the literature in individuals affected with breast cancer and in individuals undertaking colorectal or prostate cancer panel testing, as well as in healthy controls (example, Giri_2022, Pearlman_2021, Einarsdottir_2005, Tavtigian_2009, Bernstein_2010, Weitzel_2019, Purrington_2020). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or other ATM-related disorders. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 22529920, 17132159, 35666082, 34250417, 19781682, 11443540, 31206626, 32868316). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 135744). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Observed in individuals with breast, thyroid, colorectal, prostate, and/or endometrial cancer (PMID: 20305132, 29684080, 31206626, 34250417, 35666082); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22529920, 19781682, 11443540, 20305132, 29684080, 31206626, 17132159, 34250417, 35666082)
Comment:
The ATM c.2281A>T variant is predicted to result in the amino acid substitution p.Thr761Ser. This variant has been reported in patients with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626) as well as in controls without cancer (Thorstenson et al. 2001. PubMed ID 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has also been reported in a study of patients with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD and is has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135744/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline Variant Spectrum Among African American Men Undergoing Prostate Cancer Germline Testing: Need for Equity in Genetic Testing. | Giri VN | JCO precision oncology | 2022 | PMID: 35666082 |
| Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative. | Pearlman R | JCO precision oncology | 2021 | PMID: 34250417 |
| Heritable Susceptibility to Breast Cancer among African-American Women in the Detroit Research on Cancer Survivors Study. | Purrington KS | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 32868316 |
| Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. | Weitzel JN | Cancer | 2019 | PMID: 31206626 |
| 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 |
| 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 |
| Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. | George Priya Doss C | PloS one | 2012 | PMID: 22529920 |
| 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 |
| Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study. | Einarsdóttir K | Breast cancer research : BCR | 2006 | PMID: 17132159 |
| Global analysis of ATM polymorphism reveals significant functional constraint. | Thorstenson YR | American journal of human genetics | 2001 | PMID: 11443540 |
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Text-mined citations for rs2235011 ...
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 25, 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.