In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, pancreatic, and other cancers, but also in unaffected controls (PMID: 17393301, 28779002, 28652578, 29368341, 30311369, 34477817, 35047863, 36315919, 34262154, 34326862, 33471991, 33436325); This variant is associated with the following publications: (PMID: 27896999, 28569218, 28870692, 22529920, 17393301, 19781682, 22420423, 27720647, 24463458, 28500398, 27844328, 28779002, 29368341, 29449433, 23778141, 29872864, 28652578, 29106415, 29316426, 30197789, 30662270, 30814645, 31843900, 30537493, 33280026, 30311369, 32183301, 30303537, 34477817, 35047863, 36315919, 34262154, 34326862, 38451242, 33471991, 33436325, 37626821)
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.1009C>T (p.Arg337Cys)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(18); Likely benign(1)
Uncertain significance(18); Likely benign(1)
19 out of 22 submissions contributed to this 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.
22
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.1009C>T (p.Arg337Cys)
Variation ID: 127327 Accession: VCV000127327.62
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108247071 (GRCh38) [ NCBI UCSC ] 11: 108117798 (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 Feb 19, 2018 Apr 13, 2025 Mar 4, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.1009C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Arg337Cys missense NM_001351834.2:c.1009C>T NP_001338763.1:p.Arg337Cys missense NC_000011.10:g.108247071C>T NC_000011.9:g.108117798C>T NG_009830.1:g.29240C>T LRG_135:g.29240C>T LRG_135t1:c.1009C>T LRG_135p1:p.Arg337Cys Q13315:p.Arg337Cys - Protein change
- R337C
- Other names
-
p.R337C:CGT>TGT
- Canonical SPDI
- NC_000011.10:108247070: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.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00017
- 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 |
11368 | 18330 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 27, 2024 | RCV000115130.22 | |
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Feb 1, 2025 | RCV000168399.25 | |
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 27, 2024 | RCV000656756.27 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2025 | RCV000780894.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 15, 2024 | RCV005042205.1 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV001762215.9 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356891.4 |
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
(Sep 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149039.21
First in ClinVar: May 17, 2014 Last updated: Oct 08, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, pancreatic, and other cancers, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, pancreatic, and other cancers, but also in unaffected controls (PMID: 17393301, 28779002, 28652578, 29368341, 30311369, 34477817, 35047863, 36315919, 34262154, 34326862, 33471991, 33436325); This variant is associated with the following publications: (PMID: 27896999, 28569218, 28870692, 22529920, 17393301, 19781682, 22420423, 27720647, 24463458, 28500398, 27844328, 28779002, 29368341, 29449433, 23778141, 29872864, 28652578, 29106415, 29316426, 30197789, 30662270, 30814645, 31843900, 30537493, 33280026, 30311369, 32183301, 30303537, 34477817, 35047863, 36315919, 34262154, 34326862, 38451242, 33471991, 33436325, 37626821) (less)
|
|
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Uncertain significance
(Apr 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186506.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R337C variant (also known as c.1009C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide … (more)
The p.R337C variant (also known as c.1009C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. Using multiple in silico tools, this alteration was predicted to have some potential for functional significance (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). This alteration has been reported in an individual with unilateral breast cancer diagnosed before 50 years of age and an individual with prostate cancer (Broeks A et al. Breast Cancer Res. Treat. 2008 Jan;107:243-8; Velho P et al. Prostate 2018 04;78(5):401-407). This alteration has also been reported both in affected cancer individuals and in unaffected controls across several studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Tiao G et al. Leukemia, 2017 10;31:2244-2247; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
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Likely benign
(Feb 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219092.15
First in ClinVar: Mar 29, 2015 Last updated: Feb 25, 2025 |
|
|
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Uncertain significance
(May 30, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000341173.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Uncertain significance
(May 05, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000681943.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 337 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with cysteine at codon 337 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 been reported in individuals affected with breast and prostate cancer (PMID: 17393301, 19781682, 20305132, 23555315, 28779002, 29368341, 34477817), chronic lymphocytic leukemia (PMID: 28652578) and in unaffected controls (PMID: 28652578, 28779002). In addition, a large international case-control study reported this variant in 4/60462 breast cancer cases and 10/53451 controls (OR=0.354, 95%, CI 0.111 to 1.128, p-value=0.105; PMID: 33471991). This variant has been identified in 26/282550 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)
|
|
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Uncertain significance
(Oct 16, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805487.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
|
|
Uncertain significance
(Aug 18, 2023)
C
Contributing to aggregate classification
|
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: SCV000918528.4
First in ClinVar: Jun 02, 2019 Last updated: Oct 04, 2023 |
Comment:
Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.000092 (i.e. 26 heterozygotes) in 282550 control chromosomes gnomAD. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in numerous individuals affected with Breast Cancer and other tumor phenotypes that belong to the HBOC cancer spectrum (e.g. Broeks_2008, Tavtigian_2009, Bernstein_2010, Karlsson_2021, Elbracht_2021), however, it was also reported in controls (Karlsson_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 10/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.2021G>A, p.Gly674Asp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function and no occurrence of the variant in individuals affected with Ataxia-Telangiectasia has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 17393301, 33471991, 34477817, 33280026, 26085511, 33436325, 36315919, 27322425, 19781682, 28652578). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with a predominant consensus as VUS (n=13); two submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
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Uncertain significance
(May 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138444.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Oct 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001143094.3
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2025 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Computational tools predict that this variant is damaging. (less)
|
|
|
Uncertain significance
(Aug 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001775531.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
|
|
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Uncertain significance
(Nov 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010851.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Uncertain significance
(May 05, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529629.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.1009C>T (p.R337C ) variant has been reported in individuals with breast cancer (PMID: 17393301,19781682, 20305132, 28569218, 30303537, 30537493). This variant involves a highly … (more)
The ATM c.1009C>T (p.R337C ) variant has been reported in individuals with breast cancer (PMID: 17393301,19781682, 20305132, 28569218, 30303537, 30537493). This variant involves a highly conserved amino acid, and computational analyses do not provide strong support for or against an impact to the protein, though these predictions have not been confirmed by published functional studies. This variant was observed in 26/282550 chromosomes from the large and broad populations by the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 12732). Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
|
|
|
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Uncertain significance
(Dec 28, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580517.2
First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025
Comment:
ACMG criteria applied: PM2_SUP, BP4
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Uncertain significance
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024384.5
First in ClinVar: Aug 13, 2023 Last updated: Mar 11, 2025 |
|
|
|
Uncertain significance
(Oct 16, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171463.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The ATM c.1009C>T (p.Arg337Cys) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about … (more)
The ATM c.1009C>T (p.Arg337Cys) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 19781682, 30303537). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
|
|
|
Uncertain significance
(Mar 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206466.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Uncertain significance
(Feb 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219891.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 17393301 (2008), 28569218 (2017), 28779002 (2017), 30537493 (2018), 30303537 … (more)
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 17393301 (2008), 28569218 (2017), 28779002 (2017), 30537493 (2018), 30303537 (2019)), prostate cancer (PMID: 29368341 (2018)), and chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as unaffected controls (PMIDs: 28779002 (2017), 30303537 (2019)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.0002 (7/35394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Feb 27, 2024)
C
Contributing to aggregate classification
|
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: SCV005045429.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
|
|
|
Uncertain significance
(May 15, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
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:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV005681199.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
|
|
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Benign
(Sep 01, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
not specified
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV001251385.1
First in ClinVar: Jun 08, 2020 Last updated: Jun 08, 2020
Comment:
Transcript analysis by cBROCA
|
|
|
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Uncertain significance
(Sep 16, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001456876.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552173.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Arg337Cys variant was identified in 1 of 874 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Broeks 2008). The variant … (more)
The ATM p.Arg337Cys variant was identified in 1 of 874 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Broeks 2008). The variant was also identified in dbSNP (ID: rs138398778) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics), Clinvitae, Cosmic, and MutDB databases. The variant was not identified in the COGR or LOVD 3.0 databases. The variant was identified in control databases in 23 of 276952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 6 of 34376 chromosomes (freq: 0.0002), European in 13 of 126526 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg337 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Comment:
Comment:
The p.R337C variant (also known as c.1009C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. Using multiple in silico tools, this alteration was predicted to have some potential for functional significance (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). This alteration has been reported in an individual with unilateral breast cancer diagnosed before 50 years of age and an individual with prostate cancer (Broeks A et al. Breast Cancer Res. Treat. 2008 Jan;107:243-8; Velho P et al. Prostate 2018 04;78(5):401-407). This alteration has also been reported both in affected cancer individuals and in unaffected controls across several studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Tiao G et al. Leukemia, 2017 10;31:2244-2247; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This missense variant replaces arginine with cysteine at codon 337 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 been reported in individuals affected with breast and prostate cancer (PMID: 17393301, 19781682, 20305132, 23555315, 28779002, 29368341, 34477817), chronic lymphocytic leukemia (PMID: 28652578) and in unaffected controls (PMID: 28652578, 28779002). In addition, a large international case-control study reported this variant in 4/60462 breast cancer cases and 10/53451 controls (OR=0.354, 95%, CI 0.111 to 1.128, p-value=0.105; PMID: 33471991). This variant has been identified in 26/282550 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.
Comment:
Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.000092 (i.e. 26 heterozygotes) in 282550 control chromosomes gnomAD. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in numerous individuals affected with Breast Cancer and other tumor phenotypes that belong to the HBOC cancer spectrum (e.g. Broeks_2008, Tavtigian_2009, Bernstein_2010, Karlsson_2021, Elbracht_2021), however, it was also reported in controls (Karlsson_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 10/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.2021G>A, p.Gly674Asp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function and no occurrence of the variant in individuals affected with Ataxia-Telangiectasia has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 17393301, 33471991, 34477817, 33280026, 26085511, 33436325, 36315919, 27322425, 19781682, 28652578). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with a predominant consensus as VUS (n=13); two submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Computational tools predict that this variant is damaging.
Comment:
The ATM c.1009C>T (p.Arg337Cys) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 19781682, 30303537). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Comment:
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 17393301 (2008), 28569218 (2017), 28779002 (2017), 30537493 (2018), 30303537 (2019)), prostate cancer (PMID: 29368341 (2018)), and chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as unaffected controls (PMIDs: 28779002 (2017), 30303537 (2019)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.0002 (7/35394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The ATM p.Arg337Cys variant was identified in 1 of 874 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Broeks 2008). The variant was also identified in dbSNP (ID: rs138398778) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics), Clinvitae, Cosmic, and MutDB databases. The variant was not identified in the COGR or LOVD 3.0 databases. The variant was identified in control databases in 23 of 276952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 6 of 34376 chromosomes (freq: 0.0002), European in 13 of 126526 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg337 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
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:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, pancreatic, and other cancers, but also in unaffected controls (PMID: 17393301, 28779002, 28652578, 29368341, 30311369, 34477817, 35047863, 36315919, 34262154, 34326862, 33471991, 33436325); This variant is associated with the following publications: (PMID: 27896999, 28569218, 28870692, 22529920, 17393301, 19781682, 22420423, 27720647, 24463458, 28500398, 27844328, 28779002, 29368341, 29449433, 23778141, 29872864, 28652578, 29106415, 29316426, 30197789, 30662270, 30814645, 31843900, 30537493, 33280026, 30311369, 32183301, 30303537, 34477817, 35047863, 36315919, 34262154, 34326862, 38451242, 33471991, 33436325, 37626821)
Comment:
The p.R337C variant (also known as c.1009C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. Using multiple in silico tools, this alteration was predicted to have some potential for functional significance (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). This alteration has been reported in an individual with unilateral breast cancer diagnosed before 50 years of age and an individual with prostate cancer (Broeks A et al. Breast Cancer Res. Treat. 2008 Jan;107:243-8; Velho P et al. Prostate 2018 04;78(5):401-407). This alteration has also been reported both in affected cancer individuals and in unaffected controls across several studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Tiao G et al. Leukemia, 2017 10;31:2244-2247; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This missense variant replaces arginine with cysteine at codon 337 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 been reported in individuals affected with breast and prostate cancer (PMID: 17393301, 19781682, 20305132, 23555315, 28779002, 29368341, 34477817), chronic lymphocytic leukemia (PMID: 28652578) and in unaffected controls (PMID: 28652578, 28779002). In addition, a large international case-control study reported this variant in 4/60462 breast cancer cases and 10/53451 controls (OR=0.354, 95%, CI 0.111 to 1.128, p-value=0.105; PMID: 33471991). This variant has been identified in 26/282550 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.
Comment:
Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.000092 (i.e. 26 heterozygotes) in 282550 control chromosomes gnomAD. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in numerous individuals affected with Breast Cancer and other tumor phenotypes that belong to the HBOC cancer spectrum (e.g. Broeks_2008, Tavtigian_2009, Bernstein_2010, Karlsson_2021, Elbracht_2021), however, it was also reported in controls (Karlsson_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 10/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.2021G>A, p.Gly674Asp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function and no occurrence of the variant in individuals affected with Ataxia-Telangiectasia has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 17393301, 33471991, 34477817, 33280026, 26085511, 33436325, 36315919, 27322425, 19781682, 28652578). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with a predominant consensus as VUS (n=13); two submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Computational tools predict that this variant is damaging.
Comment:
The ATM c.1009C>T (p.Arg337Cys) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 19781682, 30303537). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Comment:
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 17393301 (2008), 28569218 (2017), 28779002 (2017), 30537493 (2018), 30303537 (2019)), prostate cancer (PMID: 29368341 (2018)), and chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as unaffected controls (PMIDs: 28779002 (2017), 30303537 (2019)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.0002 (7/35394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The ATM p.Arg337Cys variant was identified in 1 of 874 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Broeks 2008). The variant was also identified in dbSNP (ID: rs138398778) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics), Clinvitae, Cosmic, and MutDB databases. The variant was not identified in the COGR or LOVD 3.0 databases. The variant was identified in control databases in 23 of 276952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 6 of 34376 chromosomes (freq: 0.0002), European in 13 of 126526 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg337 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia. | Lampson BL | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2023 | PMID: 36315919 |
| 5-Hydroxymethylcytosine (5hmC) at or near cancer mutation hot spots as potential targets for early cancer detection. | Lu MJ | BMC research notes | 2022 | PMID: 35449110 |
| 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 |
| Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms. | Elbracht M | Blood advances | 2021 | PMID: 34477817 |
| Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
| Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia. | Dalmasso B | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34262154 |
| 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 |
| Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. | Karlsson Q | European urology oncology | 2021 | PMID: 33436325 |
| A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
| ATM-Deficient Cancers Provide New Opportunities for Precision Oncology. | Jette NR | Cancers | 2020 | PMID: 32183301 |
| Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
| Monitoring of cancer patients via next-generation sequencing of patient-derived circulating tumor cells and tumor DNA. | Onidani K | Cancer science | 2019 | PMID: 31169336 |
| Complete response with fluorouracil and irinotecan with a BRAF(V600E) and EGFR inhibitor in BRAF-mutated metastatic colorectal cancer: a case report. | Wang Z | OncoTargets and therapy | 2019 | PMID: 30662270 |
| Molecular characterization of metaplastic breast carcinoma via next-generation sequencing. | Zhai J | Human pathology | 2019 | PMID: 30537493 |
| Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
| Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma. | Ikeda S | The oncologist | 2018 | PMID: 29487225 |
| Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations. | Agathangelidis A | Haematologica | 2018 | PMID: 29449433 |
| Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. | Isaacsson Velho P | The Prostate | 2018 | PMID: 29368341 |
| 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 |
| Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
| A knowledge-based framework for the discovery of cancer-predisposing variants using large-scale sequencing breast cancer data. | Melloni GEM | Breast cancer research : BCR | 2017 | PMID: 28569218 |
| IDENTIFY CANCER DRIVER GENES THROUGH SHARED MENDELIAN DISEASE PATHOGENIC VARIANTS AND CANCER SOMATIC MUTATIONS. | Ma M | Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing | 2017 | PMID: 27896999 |
| Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets. | Enkner F | Pathology oncology research : POR | 2017 | PMID: 27844328 |
| Molecular driver alterations and their clinical relevance in cancer of unknown primary site. | Löffler H | Oncotarget | 2016 | PMID: 27322425 |
| Serial Next-Generation Sequencing of Circulating Cell-Free DNA Evaluating Tumor Clone Response To Molecularly Targeted Drug Administration. | Frenel JS | Clinical cancer research : an official journal of the American Association for Cancer Research | 2015 | PMID: 26085511 |
| 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 |
| 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 |
| The spectrum of ATM missense variants and their contribution to contralateral breast cancer. | Broeks A | Breast cancer research and treatment | 2008 | PMID: 17393301 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
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Record last updated Apr 13, 2025
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.