ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.7475T>G (p.Leu2492Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(18); Benign(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000051.4(ATM):c.7475T>G (p.Leu2492Arg)
Variation ID: 127446 Accession: VCV000127446.75
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108330381 (GRCh38) [ NCBI UCSC ] 11: 108201108 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 8, 2017 Oct 20, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.7475T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Leu2492Arg missense NM_001330368.2:c.641-21310A>C intron variant NM_001351110.2:c.*38+4839A>C intron variant NM_001351834.2:c.7475T>G NP_001338763.1:p.Leu2492Arg missense NC_000011.10:g.108330381T>G NC_000011.9:g.108201108T>G NG_009830.1:g.112550T>G NG_054724.1:g.144452A>C LRG_135:g.112550T>G LRG_135t1:c.7475T>G LRG_135p1:p.Leu2492Arg Q13315:p.Leu2492Arg - Protein change
- L2492R
- Other names
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p.L2492R:CTT>CGT
- Canonical SPDI
- NC_000011.10:108330380:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD) 0.00019
- 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 | ||
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HI score
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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. |
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ATM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10852 | 17462 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6592 |
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. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Apr 15, 2024 | RCV000115252.32 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000195623.35 | |
Uncertain significance (7) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2024 | RCV000488003.41 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000780920.18 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2022 | RCV000786770.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV003325459.7 | |
ATM-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jun 21, 2024 | RCV004739397.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440813.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Uncertain significance
(Nov 07, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002538004.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.7475T>G (p.L2492R) variant has been reported in at least 8 individuals with a personal or family history of breast and/or ovarian cancer as … (more)
The ATM c.7475T>G (p.L2492R) variant has been reported in at least 8 individuals with a personal or family history of breast and/or ovarian cancer as well as 1 individual with prostate cancer and 1 individual with colorectal cancer (PMID: 32606146, 28135145, 31159747, 25980754, 3030625, 20305132). This variant was also detected in 2/516 chronic lymphocytic leukemia cases and 2/8920 controls from the same study (PMID: 28652578). It was observed in 31/129020 chromosomes in the Non-Finnish European population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 127446). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Sep 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002584659.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Comment:
The ATM c.7475T>G (p.Leu2492Arg) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious … (more)
The ATM c.7475T>G (p.Leu2492Arg) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with many cancer types including breast, colorectal, prostate, pancreatic, and chronic lymphocytic leukemia (PMID: 28135145, 28652578, 30306255, 32606146, 35047863). This variant has been reported in 5 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). 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)
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Benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254145.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918571.3
First in ClinVar: Jun 02, 2019 Last updated: Mar 30, 2024 |
Comment:
Variant summary: ATM c.7475T>G (p.Leu2492Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. … (more)
Variant summary: ATM c.7475T>G (p.Leu2492Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251282 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (9.9e-05 vs 0.001), allowing no conclusion about variant significance. c.7475T>G has been reported in the literature primarily as a VUS in settings of multigene panel testing in individuals affected with breast, prostate, and other cancers and also in healthy controls (e.g. Bernstein_2010, Greenman_2007, Lu_2015, Tiao_2017, Young_2016, Yurgelun_2015, Yurgelun_2017, Bonache_2018, Tsaousis_2019, Holeckova_2020, Krivokuca_2022, Paduano_2022). In addition, the variant was found in 5/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 30306255, 17344846, 32606146, 34284872, 26689913, 35886069, 28652578, 31159747, 26787654, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 127446). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000172858.11
First in ClinVar: Aug 06, 2014 Last updated: Aug 11, 2024 |
Comment:
The p.L2492R variant (also known as c.7475T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide … (more)
The p.L2492R variant (also known as c.7475T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide position 7475. The leucine at codon 2492 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in multiple cohorts of individuals referred for genetic testing (Lu C et al. Nat Commun. 2015 Dec;6:10086; Tiao G et al. Leukemia. 2017 10;31:2244-2247; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jul 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000679694.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Uncertain significance
(May 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745132.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Uncertain significance
(May 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800168.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821871.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Feb 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000706050.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
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Uncertain significance
(Jan 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160197.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The ATM c.7475T>G; p.Leu2492Arg variant (rs56399857) is reported in the literature in individuals with colorectal cancer (Yurgelun 2017), chronic lymphocytic leukemia (Tiao 2017), and glioblastoma … (more)
The ATM c.7475T>G; p.Leu2492Arg variant (rs56399857) is reported in the literature in individuals with colorectal cancer (Yurgelun 2017), chronic lymphocytic leukemia (Tiao 2017), and glioblastoma multiforme (Lu 2015). This variant is reported with uncertain significance by multiple laboratories in ClinVar (Variation ID: 127446). It is found in the general population with an overall allele frequency of 0.01% (32/282684 alleles) in the Genome Aggregation Database. The leucine at codon 2492 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Tiao G et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017 Oct;31(10):2244-2247. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. (less)
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Uncertain significance
(Sep 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002071001.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.7475T>G, in exon 50 that results in an amino acid change, p.Leu2492Arg. This sequence … (more)
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.7475T>G, in exon 50 that results in an amino acid change, p.Leu2492Arg. This sequence change has been described in the gnomAD database with a frequency of 0.024% in the European (Non-Finnish) subpopulation (dbSNP rs56399857). The p.Leu2492Arg change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Leu2492Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously identified in individuals who have undergone hereditary cancer genetic testing (PMID: 31159747, 25980754) and in an individual with a history of unilateral breast cancer (PMID: 20305132) and in an individual with a history colon cancer (28135145). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu2492Arg change remains unknown at this time. (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010783.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Mar 30, 2022)
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criteria provided, single submitter
Method: research
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Astroblastoma, MN1-altered
Affected status: yes
Allele origin:
maternal
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Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital
Accession: SCV004012942.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Zygosity: Single Heterozygote
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Uncertain significance
(Jan 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046107.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in a control individual and in individuals affected with breast cancer (PMID: 30306255 (2018), 28779002 (2017), … (more)
In the published literature, this variant has been reported in a control individual and in individuals affected with breast cancer (PMID: 30306255 (2018), 28779002 (2017), 20305132 (2010)), ovarian cancer (PMID: 30441849 (2018)), lung adenocarcinoma (PMID: 17344846 (2007)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), glioblastoma (PMID: 26689913 (2015)), prostate cancer (PMID: 32606146 (2020)), and Lynch syndrome-associated cancer and/or polyps (PMID: 28135145 (2017), 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.00039 (13/33062 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)
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Likely benign
(May 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537541.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760694.4
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
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Uncertain significance
(Jul 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149161.19
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, colon, 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, colon, and other cancers (PMID: 17344846, 26689913, 28779002, 28652578, 28135145, 30306255, 29522266, 30441849, 29684080, 32606146, 35347810, 35886069, 35127508, 36029002); Present at similar frequency among breast cancer cases and controls in a large case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 35347810, 35127508, 35886069, 22529920, 17344846, 26689913, 25980754, 26787654, 22173549, 28873162, 28135145, 28652578, 26206375, 29522266, 28779002, 29684080, 30306255, 31159747, 31422574, 20305132, 30441849, 31920950, 32606146, 35047863, 36011273, 34284872, 23532176, 34718612, 33471991, 34262154, 35980532, 36029002, 37351993) (less)
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Uncertain significance
(Jul 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000574909.32
First in ClinVar: May 08, 2017 Last updated: Oct 20, 2024 |
Comment:
ATM: PM2
Number of individuals with the variant: 3
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952801.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000732995.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807307.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Uncertain significance
(Jun 21, 2024)
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no assertion criteria provided
Method: clinical testing
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ATM-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005360115.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ATM c.7475T>G variant is predicted to result in the amino acid substitution p.Leu2492Arg. This variant has been reported in individuals with breast cancer, ovarian … (more)
The ATM c.7475T>G variant is predicted to result in the amino acid substitution p.Leu2492Arg. This variant has been reported in individuals with breast cancer, ovarian cancer, chronic lymphocytic leukemia, colorectal cancer, lynch syndrome, and glioblastoma multiforme (Table S1, Bernstein et al. 2010. PubMed ID: 20305132; Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S12, Lu et al. 2015. PubMed ID: 26689913Table S5, Decker et al. Decker et al. 2017. PubMed ID: 28779002; Table S3, Tiao et al. 2017. PubMed ID: 28652578; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table 2, Bonache et al. 2018. PubMed ID: 30306255; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849; Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance by the vast majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/127446/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely pathogenic
(Jun 27, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
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Clinical Cancer Genetics and Family Consultants, Athens Medical Center
Accession: SCV000924666.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
This variant is denoted ATM c.7475T>G at the cDNA level, p.Leu2492Arg at the protein level, and is a non-conservative amino acid change located in the … (more)
This variant is denoted ATM c.7475T>G at the cDNA level, p.Leu2492Arg at the protein level, and is a non-conservative amino acid change located in the PIK-related kinase, FAT domain (Stracker 2013) of the encoded protein sequence. Five of five in silico tools predict a damaging effect of this variant on protein function. This is a rare variant (ExAC 0.00006), and has been reported in various cancers (Lu 2015, Greenman 2007, Berstein 2010). We report this variant to occur in two sisters, both heterozygotes, with breast cancer, of 47 and 50 years old. The second one also developed thyroid cancer at the age of 55. A third sister tested, is a healthy non-carrier at the age of 59 years old. The family on the paternal side included one case of breast cancer at the age of 70 years old, and another one with breast and thyroid cancer at the age of 40 and 65 years old respectively. For these reasons, this variant may be causative of disease in this family and we classify it as probably pathogenic. (less)
Number of individuals with the variant: 2
Zygosity: Homozygote, Single Heterozygote
Age: 47-50 years
Sex: female
Ethnicity/Population group: Greek
Geographic origin: Greece
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy. | Paduano F | Genes | 2022 | PMID: 35886069 |
Mutational profile of hereditary breast and ovarian cancer - Establishing genetic testing guidelines in a developing country. | Krivokuca A | Current problems in cancer | 2022 | PMID: 34284872 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer. | Holeckova K | In vivo (Athens, Greece) | 2020 | PMID: 32606146 |
Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia. | Pogoda M | Frontiers in neurology | 2019 | PMID: 31920950 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients. | Koczkowska M | Cancers | 2018 | PMID: 30441849 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
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 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
GESPA: classifying nsSNPs to predict disease association. | Khurana JK | BMC bioinformatics | 2015 | PMID: 26206375 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
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 |
Patterns of somatic mutation in human cancer genomes. | Greenman C | Nature | 2007 | PMID: 17344846 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM | - | - | - | - |
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Text-mined citations for rs56399857 ...
HelpRecord last updated Dec 07, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.