ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.8246A>T (p.Lys2749Ile)
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(9); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.8246A>T (p.Lys2749Ile)
Variation ID: 230416 Accession: VCV000230416.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108335939 (GRCh38) [ NCBI UCSC ] 11: 108206666 (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 Dec 6, 2016 May 1, 2024 Oct 3, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000051.4:c.8246A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Lys2749Ile missense NM_001330368.2:c.641-26868T>A intron variant NM_001351110.2:c.695-647T>A intron variant NM_001351834.2:c.8246A>T NP_001338763.1:p.Lys2749Ile missense NC_000011.10:g.108335939A>T NC_000011.9:g.108206666A>T NG_009830.1:g.118108A>T NG_054724.1:g.138894T>A LRG_135:g.118108A>T LRG_135t1:c.8246A>T LRG_135p1:p.Lys2749Ile - Protein change
- K2749I
- Other names
- -
- Canonical SPDI
- NC_000011.10:108335938:A:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
- 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 |
10994 | 17704 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6691 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 6, 2023 | RCV000223476.18 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 3, 2023 | RCV003441794.1 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 28, 2022 | RCV000347894.23 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Sep 21, 2023 | RCV003469000.1 | |
Likely benign (1) |
criteria provided, single submitter
|
May 22, 2021 | RCV001526927.9 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 1, 2019 | RCV001030605.9 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 20, 2023 | RCV003491969.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000367068.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
Uncertain significance
(May 01, 2019)
|
criteria provided, single submitter
Method: research
|
Hereditary breast and ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193490.2
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
|
|
Uncertain significance
(May 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000911605.4
First in ClinVar: May 20, 2019 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces lysine with isoleucine at codon 2749 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces lysine with isoleucine at codon 2749 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with pancreatic cancer (PMID: 26692440), leukemia (PMID: 27959900), breast fibroadenoma (PMID: 30851086), or breast cancer (PMID: 30851086). This variant has also been identified in 8/251016 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy controls (PMID: 30851086). 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)
|
|
Uncertain significance
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838610.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
Uncertain significance
(Oct 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000547049.8
First in ClinVar: Dec 06, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2749 of the ATM protein (p.Lys2749Ile). … (more)
This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2749 of the ATM protein (p.Lys2749Ile). This variant is present in population databases (rs779145081, gnomAD 0.04%). This missense change has been observed in individual(s) with pancreatic cancer and breast cancer, as well as in unaffected controls (PMID: 26692440, 30287823, 30851086). ClinVar contains an entry for this variant (Variation ID: 230416). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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)
|
|
Uncertain significance
(Jan 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273961.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.K2749I variant (also known as c.8246A>T), located in coding exon 55 of the ATM gene, results from an A to T substitution at nucleotide … (more)
The p.K2749I variant (also known as c.8246A>T), located in coding exon 55 of the ATM gene, results from an A to T substitution at nucleotide position 8246. The lysine at codon 2749 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was identified in the germline of an individual with pancreatic ductal adenocarcinoma diagnosed at age 37 (Ohmoto A et al. Pancreas, 2016 08;45:1056-61). This alteration has also been detected in a Chinese patient with breast fibroadenoma (Xie SN et al. Cancer Med, 2019 05;8:2372-2379). This alteration was observed in with an allele frequency of 0.00468 in 7051 unselected female breast cancer patients and was observed with an allele frequency of 0.004 in 11241 female controls of Japanese ancestry. In addition, it was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0042 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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)
|
|
Likely benign
(May 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001737690.1
First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021 |
Comment:
Variant summary: ATM c.8246A>T (p.Lys2749Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ATM c.8246A>T (p.Lys2749Ile) results in a non-conservative amino acid change in 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 0.00058 in 345640 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8246A>T has been reported in the literature in individuals affected with Pancreatic ductal adenocarcinoma (Ohmoto_2016), breast cancer (Momozawa_2018), breast fibroadenomas (Xie_2019), colorectal cancer (Fujita_2020) and unaffected controls (Momozawa_2018, Fujita_2020). At-least one recent study evaluating population screening for hereditary colorectal cancer classified this variant as benign in the Japanese population (Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
Uncertain significance
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004169105.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer, breast cancer, prostate cancer, childhood-onset acute myeloid leukemia, and another with pancreatic cancer, but also in unaffected controls (Wang et al., 2015; Ohmoto et al., 2016; Momozawa et al., 2018; Fujita et al., 2020; So et al., 2022); Stracker TH et al. (2013) Front Genet. 4 :37 (PMID: 23532176); Wang X et al. (2015) Haematologica. 100 (10):e398-401 (PMID: 26022708); Ohmoto A et al. (2016) Pancreas. 45 (7):1056-61 (PMID: 26692440); Momozawa Y et al. (2018) Nat Commun. 9 (1):4083 (PMID: 30287823); Fujita M et al. (2020) Clin Gastroenterol Hepatol. (PMID: 33309985); So MK et al. (2022) Investig Clin Urol. 63 (3):294-300 (PMID: 35534218); This variant is associated with the following publications: (PMID: 26022708, 27959900, 27602761, 26692440, 23532176, 32566746, 35171259, 30851086, 30287823, 35534218, 36243179, 33309985) (less)
|
|
Uncertain significance
(Sep 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209416.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Uncertain significance
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239549.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462606.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. | Fujita M | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2022 | PMID: 33309985 |
The genomic mutation spectrums of breast fibroadenomas in Chinese population by whole exome sequencing analysis. | Xie SN | Cancer medicine | 2019 | PMID: 30851086 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Clinicopathologic Features and Germline Sequence Variants in Young Patients (≤40 Years Old) With Pancreatic Ductal Adenocarcinoma. | Ohmoto A | Pancreas | 2016 | PMID: 26692440 |
Text-mined citations for rs779145081 ...
HelpRecord last updated Feb 08, 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.