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NM_000051.4(ATM):c.2476A>C (p.Ile826Leu)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(7)

Review status:
criteria provided, conflicting interpretations
Submissions:
9 (Most recent: Nov 4, 2021)
Last evaluated:
Nov 3, 2021
Accession:
VCV000142345.15
Variation ID:
142345
Description:
single nucleotide variant
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NM_000051.4(ATM):c.2476A>C (p.Ile826Leu)

Allele ID
152059
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
11q22.3
Genomic location
11: 108267180 (GRCh38) GRCh38 UCSC
11: 108137907 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000011.9:g.108137907A>C
LRG_135:g.49349A>C
LRG_135t1:c.2476A>C LRG_135p1:p.Ile826Leu
... more HGVS
Protein change
I826L
Other names
-
Canonical SPDI
NC_000011.10:108267179:A:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Links
ClinGen: CA168126
dbSNP: rs587782397
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 3 criteria provided, multiple submitters, no conflicts Oct 28, 2020 RCV000168043.10
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Apr 7, 2021 RCV000484154.4
Uncertain significance 1 criteria provided, single submitter Aug 13, 2021 RCV000779790.2
Uncertain significance 1 criteria provided, single submitter Nov 3, 2021 RCV001762310.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Jul 9, 2020 RCV000131419.7
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
ATM Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
6424 10317

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jul 09, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000186399.6
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (4)
Comment:
The p.I826L variant (also known as c.2476A>C), located in coding exon 16 of the ATM gene, results from an A to C substitution at nucleotide … (more)
Uncertain significance
(Oct 28, 2020)
criteria provided, single submitter
Method: clinical testing
Ataxia-telangiectasia syndrome
Allele origin: germline
Invitae
Accession: SCV000218696.10
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces isoleucine with leucine at codon 826 of the ATM protein (p.Ile826Leu). The isoleucine residue is weakly conserved and there is a … (more)
Uncertain significance
(May 16, 2018)
criteria provided, single submitter
Method: clinical testing
Ataxia-telangiectasia syndrome
Allele origin: unknown
Counsyl
Accession: SCV000799988.1
Submitted: (Jul 10, 2018)
Evidence details
Likely benign
(Aug 06, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000910809.1
Submitted: (Nov 06, 2018)
Evidence details
Uncertain significance
(Aug 13, 2021)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916592.2
Submitted: (Apr 24, 2019)
Evidence details
Publications
PubMed (4)
Comment:
Variant summary: ATM c.2476A>C (p.Ile826Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Uncertain significance
(Dec 03, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: unknown
Athena Diagnostics Inc
Accession: SCV001143100.2
Submitted: (Sep 13, 2021)
Evidence details
Publications
PubMed (7)
Uncertain significance
(Apr 07, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000566330.4
Submitted: (Sep 24, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter … (more)
Uncertain significance
(Nov 03, 2021)
criteria provided, single submitter
Method: clinical testing
Familial cancer of breast
Allele origin: germline
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010840.1
Submitted: (Nov 04, 2021)
Evidence details
Uncertain significance
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Ataxia-telangiectasia
Allele origin: germline
Natera, Inc.
Accession: SCV001462072.1
Submitted: (Dec 28, 2020)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Rare, protein-truncating variants in <i>ATM</i>, <i>CHEK2</i> and <i>PALB2</i>, but not <i>XRCC2</i>, 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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres. Navrkalova V Haematologica 2016 PMID: 27479817
Patterns and functional implications of rare germline variants across 12 cancer types. Lu C Nature communications 2015 PMID: 26689913
ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. Guarini A Haematologica 2012 PMID: 21993670
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
ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy. Paglia LL Breast cancer research and treatment 2010 PMID: 19404735

Text-mined citations for rs587782397...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 04, 2021