This variant is denoted ATM c.4201T>A at the cDNA level, p.Leu1401Ile (L1401I) at the protein level, and results in the change of a Leucine to an Isoleucine (TTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1401Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1401Ile occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Leu1401Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.4201T>A (p.Leu1401Ile)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)
Uncertain significance(4); Likely benign(1)
5 out of 8 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.
8
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.4201T>A (p.Leu1401Ile)
Variation ID: 127383 Accession: VCV000127383.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108289068 (GRCh38) [ NCBI UCSC ] 11: 108159795 (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 May 29, 2016 Jul 13, 2025 Mar 20, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.4201T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Leu1401Ile missense NM_001351834.2:c.4201T>A NP_001338763.1:p.Leu1401Ile missense NC_000011.10:g.108289068T>A NC_000011.9:g.108159795T>A NG_009830.1:g.71237T>A LRG_135:g.71237T>A LRG_135t1:c.4201T>A LRG_135p1:p.Leu1401Ile - Protein change
- L1401I
- Other names
-
p.L1401I:TTA>ATA
- Canonical SPDI
- NC_000011.10:108289067:T:A
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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 |
11736 | 18942 | |
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
|
Jun 6, 2022 | RCV000115188.7 | |
| Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
|
Mar 20, 2025 | RCV000568754.11 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Jan 30, 2025 | RCV000468550.7 |
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
(Feb 19, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000149097.13
First in ClinVar: May 17, 2014 Last updated: May 29, 2016 |
Comment:
show
This variant is denoted ATM c.4201T>A at the cDNA level, p.Leu1401Ile (L1401I) at the protein level, and results in the change of a Leucine to an Isoleucine (TTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1401Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1401Ile occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Leu1401Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. (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
(Jun 06, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Athena Diagnostics
Accession: SCV002771853.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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
(Jan 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ataxia-telangiectasia syndrome |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000547021.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1401 of the ATM protein (p.Leu1401Ile). This variant is present in population databases (rs587779838, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127383). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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
|
|
|
Uncertain significance
(Dec 20, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000906687.5
First in ClinVar: May 20, 2019 Last updated: May 03, 2025 |
Comment:
show
This missense variant replaces leucine with isoleucine at codon 1401 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. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 2/53459 controls (OR=0.221, 95%CI 0.01 to 4.902, p-value=0.22; PMID: 33471991). This variant has been identified in 4/250996 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
(Mar 20, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000660496.7
First in ClinVar: Jan 01, 2018 Last updated: Jul 13, 2025 |
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
(Aug 09, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ataxia-telangiectasia |
Natera, Inc.
Accession: SCV002079269.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034325.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037930.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1401 of the ATM protein (p.Leu1401Ile). This variant is present in population databases (rs587779838, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127383). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces leucine with isoleucine at codon 1401 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. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 2/53459 controls (OR=0.221, 95%CI 0.01 to 4.902, p-value=0.22; PMID: 33471991). This variant has been identified in 4/250996 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:
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.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs587779838 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 12, 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.