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.
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 (17); Likely benign (3)
Uncertain significance (17); Likely benign (3)
20 out of 23 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.
23
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: VCV000127327.67
- 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 Mar 7, 2026 Jan 31, 2026 - 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
-
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 |
12193 | 19653 | |
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 classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Nov 14, 2025 | RCV000115130.25 | |
| Conflicting classifications of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 31, 2026 | RCV000168399.27 | |
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 27, 2024 | RCV000656756.27 | |
| Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 29, 2025 | RCV000780894.16 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356891.4 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV001762215.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 15, 2024 | RCV005042205.1 |
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. |
Expand all rows
Collapse all rows
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 16, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
PreventionGenetics, part of Exact Sciences
Accession: SCV000805487.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Feb 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219891.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(Dec 28, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
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
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: female
|
|
|
Uncertain significance
(Mar 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Baylor Genetics
Accession: SCV004206466.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(Oct 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Athena Diagnostics
Accession: SCV001143094.3
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2025 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Likely benign
(Jan 31, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ataxia-telangiectasia syndrome |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219092.16
First in ClinVar: Mar 29, 2015 Last updated: Mar 07, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Nov 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
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 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
|
|
|
Uncertain significance
(Feb 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005045429.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Sep 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000149039.21
First in ClinVar: May 17, 2014 Last updated: Oct 08, 2024 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(May 15, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
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. |
Fulgent Genetics, Fulgent Genetics
Accession: SCV005681199.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jun 13, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000681943.7
First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025 |
Comment:
show
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. 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Likely benign
(Jul 07, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918528.6
First in ClinVar: Jun 02, 2019 Last updated: Nov 02, 2025 |
Comment:
show
Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 8.9e-05 in 1613688 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database (v4) is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.0001). 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). ClinVar contains an entry for this variant (Variation ID: 127327). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Nov 14, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000186506.11
First in ClinVar: Aug 06, 2014 Last updated: Jan 11, 2026 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(May 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ataxia-telangiectasia syndrome |
Mendelics
Accession: SCV001138444.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(Aug 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ataxia-telangiectasia syndrome |
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001775531.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(May 05, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
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)
|
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Oct 16, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
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:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(May 30, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000341173.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Sex: mixed
|
|
|
Uncertain significance
(Nov 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
|
Molecular Pathology, Peter Maccallum Cancer Centre
Accession: SCV006277842.1
First in ClinVar: Jul 13, 2025 Last updated: Jul 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Dec 29, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024384.6
First in ClinVar: Aug 13, 2023 Last updated: Jan 03, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Sep 01, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
King Laboratory, University of Washington
Accession: SCV001251385.1
First in ClinVar: Jun 08, 2020 Last updated: Jun 08, 2020
Comment:
Transcript analysis by cBROCA
|
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Sep 16, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ataxia-telangiectasia |
Natera, Inc.
Accession: SCV001456876.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Malignant tumor of breast |
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:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
Comment:
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:
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:
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. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 8.9e-05 in 1613688 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database (v4) is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.0001). 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). ClinVar contains an entry for this variant (Variation ID: 127327). Based on the evidence outlined above, the variant was classified as likely benign.
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:
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:
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, 2026
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.