ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.2275A>G (p.Ser759Gly)
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(12); 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.2275A>G (p.Ser759Gly)
Variation ID: 127346 Accession: VCV000127346.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108257505 (GRCh38) [ NCBI UCSC ] 11: 108128232 (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 Dec 6, 2016 Oct 20, 2024 Jun 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.2275A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Ser759Gly missense NM_001351834.2:c.2275A>G NP_001338763.1:p.Ser759Gly missense NC_000011.10:g.108257505A>G NC_000011.9:g.108128232A>G NG_009830.1:g.39674A>G LRG_135:g.39674A>G LRG_135t1:c.2275A>G LRG_135p1:p.Ser759Gly - Protein change
- S759G
- Other names
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p.S759G:AGT>GGT
- Canonical SPDI
- NC_000011.10:108257504:A: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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Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- 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 |
10836 | 17434 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000115151.20 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000205470.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2017 | RCV000515206.5 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2024 | RCV000589762.23 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2023 | RCV001798310.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 8, 2024 | RCV003460800.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 10, 2023 | RCV002469010.3 |
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
(May 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611350.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Uncertain significance
(Jan 12, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000367035.3
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)
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Uncertain significance
(May 06, 2022)
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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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Athena Diagnostics
Accession: SCV002771660.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 10, 2023)
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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: SCV000694214.3
First in ClinVar: Mar 17, 2018 Last updated: Aug 26, 2023 |
Comment:
Variant summary: ATM c.2275A>G (p.Ser759Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: ATM c.2275A>G (p.Ser759Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251174 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2275A>G has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (example: Caminsky_2016, Tung-2016). 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. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 21787400, 25186627, 26689913, 26898890, 26976419, 31422574, 36315919).All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002041960.2
First in ClinVar: Dec 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 04, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000682046.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with glycine at codon 759 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with glycine at codon 759 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26689913, 26898890, 26976419), pancreatic cancer (PMID: 28726808), and chronic lymphocytic leukemia (PMID: 28652578). This variant has been identified in 9/282588 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)
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Uncertain significance
(Nov 16, 2023)
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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: SCV000183888.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.S759G variant (also known as c.2275A>G), located in coding exon 14 of the ATM gene, results from an A to G substitution at nucleotide … (more)
The p.S759G variant (also known as c.2275A>G), located in coding exon 14 of the ATM gene, results from an A to G substitution at nucleotide position 2275. The serine at codon 759 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts, including in an individual with ovarian cancer and a BRCA1 pathogenic variant (Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Caminsky NG et al. Hum Mutat, 2016 07;37:640-52; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was also reported in 1/302 individuals with both a personal and family history of pancreatic cancer (Chaffee KG et al. Genet Med, 2018 01;20:119-127). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Feb 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206322.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Jun 26, 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: SCV000149060.20
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast, pancreatic, or other cancers (PMID: 21787400, 26689913, 26898890, 26976419, 28726808, 32885271, 34326862); This variant is associated with the following publications: (PMID: 21787400, 26976419, 26898890, 28726808, 31422574, 26689913, 32885271, 34994613, 25186627, 36315919, 34326862) (less)
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Uncertain significance
(Feb 24, 2022)
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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: SCV002529820.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.2275A>G (p.S759G) has been reported as heterozygous in at least 7 individuals with breast cancer, pancreatic cancer, or small intestine neuroendocrine cancer (PMID: … (more)
The ATM c.2275A>G (p.S759G) has been reported as heterozygous in at least 7 individuals with breast cancer, pancreatic cancer, or small intestine neuroendocrine cancer (PMID: 21787400, 25186627, 26689913, 26898890, 26976419, 28726808, 34994613). This variant was observed in 9/129144 chromosomes in the European (non-Finnish) population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID: 127346). 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)
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Uncertain significance
(Jan 25, 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: SCV000259588.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 759 of the ATM protein (p.Ser759Gly). … (more)
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 759 of the ATM protein (p.Ser759Gly). This variant is present in population databases (rs148705269, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, low grade glioma, ovarian cancer, pancreatic cancer, and/or uterine cancer (PMID: 26689913, 26898890, 26976419, 28726808, 34326862, 36315919). ClinVar contains an entry for this variant (Variation ID: 127346). 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 tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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)
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Likely benign
(May 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV005083879.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(Apr 01, 2022)
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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: SCV004133248.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
ATM: PM2, BP4
Number of individuals with the variant: 1
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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:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550722.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Ser759Gly variant was identified in 3 of 1550 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Caminsky 2016, Tung 2016). … (more)
The ATM p.Ser759Gly variant was identified in 3 of 1550 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Caminsky 2016, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs148705269) as "With Uncertain significance allele", ClinVar (6x uncertain significance), and Clinvitae (3x uncertain significance). The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 8 of 276952 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 8 of 126678 chromosomes (freq: 0.00006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser759 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(Mar 20, 2020)
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no assertion criteria provided
Method: clinical testing
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Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002079628.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia. | Lampson BL | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2023 | PMID: 36315919 |
Clinical Implications of Pathogenic Germline Variants in Small Intestine Neuroendocrine Tumors (SI-NETs). | Perez K | JCO precision oncology | 2021 | PMID: 34994613 |
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort. | Kraemer D | Swiss medical weekly | 2019 | PMID: 31422574 |
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. | Chaffee KG | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28726808 |
Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. | Caminsky NG | Human mutation | 2016 | PMID: 26898890 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Rare variants in the ATM gene and risk of breast cancer. | Goldgar DE | Breast cancer research : BCR | 2011 | PMID: 21787400 |
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Text-mined citations for rs148705269 ...
HelpRecord last updated Oct 20, 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.