ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.737A>G (p.Asn246Ser)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.737A>G (p.Asn246Ser)
Variation ID: 524424 Accession: VCV000524424.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108244862 (GRCh38) [ NCBI UCSC ] 11: 108115589 (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 28, 2018 Feb 20, 2024 Jan 24, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000051.4:c.737A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Asn246Ser missense NM_001351834.2:c.737A>G NP_001338763.1:p.Asn246Ser missense NC_000011.10:g.108244862A>G NC_000011.9:g.108115589A>G NG_009830.1:g.27031A>G LRG_135:g.27031A>G LRG_135t1:c.737A>G LRG_135p1:p.Asn246Ser - Protein change
- N246S
- Other names
- -
- Canonical SPDI
- NC_000011.10:108244861:A:G
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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 |
10341 | 16658 |
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 24, 2024 | RCV000628206.8 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 27, 2021 | RCV001311783.9 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 9, 2018 | RCV000779770.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 10, 2023 | RCV003459481.1 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 14, 2022 | RCV002257863.4 |
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
(Feb 09, 2018)
|
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: SCV000916559.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: ATM c.737A>G (p.Asn246Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: ATM c.737A>G (p.Asn246Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245766 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.737A>G in individuals affected with breast cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000749100.5
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 246 of the ATM protein (p.Asn246Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 246 of the ATM protein (p.Asn246Ser). This variant is present in population databases (rs781023264, gnomAD 0.003%). This missense change has been observed in individual(s) with early-onset breast cancer and/or male breast cancer (PMID: 30613976, 33785725). ClinVar contains an entry for this variant (Variation ID: 524424). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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
(Apr 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001802861.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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)
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 protein structure/function; Identified in a patient with breast cancer (Gervas et al., 2021); This variant is associated with the following publications: (PMID: 33785725, 30287823) (less)
|
|
Uncertain significance
(Jan 06, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537659.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.737A>G (p.N246S) variant has been reported in several individuals with breast cancer (PMID: 30613976, 33785725, 33471991, 30287823), as well as in a healthy … (more)
The ATM c.737A>G (p.N246S) variant has been reported in several individuals with breast cancer (PMID: 30613976, 33785725, 33471991, 30287823), as well as in a healthy people (PMID: 32980694). It was observed in 1/30610 chromosomes in the South Asian population in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID 524424). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
Uncertain significance
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002672098.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.N246S variant (also known as c.737A>G), located in coding exon 6 of the ATM gene, results from an A to G substitution at nucleotide … (more)
The p.N246S variant (also known as c.737A>G), located in coding exon 6 of the ATM gene, results from an A to G substitution at nucleotide position 737. The asparagine at codon 246 is replaced by serine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Rizzolo P et al. Int J Cancer, 2019 07;145:390-400; Gervas P et al. Exp Oncol, 2021 03;43:52-55). This alteration was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206958.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Uncertain significance
(Oct 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003827461.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Jun 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357874.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces asparagine with serine at codon 246 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces asparagine with serine at codon 246 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 3/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 33785725). This variant has been identified in 1/251014 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)
|
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 |
---|---|---|---|---|
New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients. | Gervas P | Experimental oncology | 2021 | PMID: 33785725 |
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 |
Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. | Rizzolo P | International journal of cancer | 2019 | PMID: 30613976 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. | Hauke J | Cancer medicine | 2018 | PMID: 29522266 |
Text-mined citations for rs781023264 ...
HelpRecord last updated May 08, 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.