ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.4375G>A (p.Gly1459Arg)
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(14); 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.4375G>A (p.Gly1459Arg)
Variation ID: 127387 Accession: VCV000127387.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108289740 (GRCh38) [ NCBI UCSC ] 11: 108160467 (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 Nov 11, 2017 Oct 26, 2024 Aug 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.4375G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Gly1459Arg missense NM_001351834.2:c.4375G>A NP_001338763.1:p.Gly1459Arg missense NC_000011.10:g.108289740G>A NC_000011.9:g.108160467G>A NG_009830.1:g.71909G>A LRG_135:g.71909G>A LRG_135t1:c.4375G>A LRG_135p1:p.Gly1459Arg - Protein change
- G1459R
- Other names
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p.G1459R:GGA>AGA
- Canonical SPDI
- NC_000011.10:108289739:G:A
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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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Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00014
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 |
10839 | 17439 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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May 27, 2024 | RCV000115192.24 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 27, 2024 | RCV000196015.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 10, 2022 | RCV000515274.4 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 2, 2024 | RCV000586694.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 19, 2018 | RCV001249852.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 19, 2024 | RCV001824608.7 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 17, 2024 | RCV003460803.3 | |
ATM-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Aug 1, 2023 | RCV004549552.1 |
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. |
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Uncertain significance
(Nov 28, 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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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV004228041.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
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Uncertain significance
(Jan 27, 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: SCV000254105.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1459 of the ATM protein (p.Gly1459Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1459 of the ATM protein (p.Gly1459Arg). This variant is present in population databases (rs145667735, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 17623063, 25980754, 26976419, 29458332, 30374176, 33436325). ClinVar contains an entry for this variant (Variation ID: 127387). 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. 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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Uncertain significance
(Dec 27, 2022)
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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: SCV000682200.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 1459 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glycine with arginine at codon 1459 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. The variant has been reported in individuals affected with breast cancer (PMID: 17623063, 26976419, 28779002, 33471991), prostate cancer (PMID: 33436325), colorectal cancer (PMID: 29458332), an individual suspected of Lynch syndrome (PMID: 25980754), and in healthy controls (PMID: 19781682, 28779002, 33471991). This variant has also been identified in 16/282612 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
(May 27, 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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Ambry Genetics
Accession: SCV000186391.11
First in ClinVar: Aug 06, 2014 Last updated: Aug 11, 2024 |
Comment:
The p.G1459R variant (also known as c.4375G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide … (more)
The p.G1459R variant (also known as c.4375G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4375. The glycine at codon 1459 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in individuals diagnosed with breast cancer and healthy controls across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Edvardsen H et al. Radiat Oncol. 2007 Jul;2:25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
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Uncertain significance
(Oct 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Breast and Ovarian Cancer Syndrome
Affected status: yes
Allele origin:
germline
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Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV001424014.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1459 in the ATM … (more)
This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1459 in the ATM protein. This is a previously reported variant (ClinVar) that has been observed in at least one breast cancer patient (PMID 26976419), two patients being tested for Lynch syndrome (PMID 25980754), a patient with familial colorectal cancer (PMID 29458332), and one healthy control with no cancer (PMID 19781682). This variant is rare in control population datasets (gnomAD database, 16/276984 alleles, .006% overall frequency). A meta-analysis in breast cancer patients did not identify any enrichment of this variant in breast cancer cases versus healthy controls (PMID 19781682). The Gly1459 residue is not located in a known functional domain, and studies assessing the effect of this variant on ATM function are not published in the literature, to our knowledge. However, multiple in silico tools queried predict that this glycine to arginine amino acid change would be damaging. The glycine at this position is highly evolutionarily conserved across mammalian species examined. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider the significance of this variant to be uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 06, 2021)
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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: SCV002534690.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.4375G>A (p.G1459R) variant has been reported in heterozygosity in several individuals with breast cancer (PMID: 17623063, 26976419, 28779002, 30374176, 33471991). The variant has … (more)
The ATM c.4375G>A (p.G1459R) variant has been reported in heterozygosity in several individuals with breast cancer (PMID: 17623063, 26976419, 28779002, 30374176, 33471991). The variant has also been reported in patients undergoing testing for Lynch syndrome related diagnoses (PMID: 25980754, 29458332), as well as healthy controls (PMID: 19781682, 33471991, FLOSSIES Database). It was observed in 15/129048 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID 127387). 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
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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ATM-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805561.2
First in ClinVar: Sep 13, 2018 Last updated: Nov 20, 2023 |
Comment:
The ATM c.4375G>A variant is predicted to result in the amino acid substitution p.Gly1459Arg. This variant has been documented in individuals with suspected Lynch syndrome … (more)
The ATM c.4375G>A variant is predicted to result in the amino acid substitution p.Gly1459Arg. This variant has been documented in individuals with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Dominguez-Valentin et al. 2018. PubMed ID: 29458332), breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Additional File 1, Edvardsen et al. 2007. PubMed ID: 17623063), and prostate cancer (Table S4, Karlsson et al. 2021. PubMed ID: 33436325). However, Tavtigian et al. has observed this variant only in the control group in a large case-control-based study on breast cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160467-G-A). In ClinVar, it is classified as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127387/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Apr 11, 2023)
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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: SCV001143109.3
First in ClinVar: Jan 19, 2020 Last updated: Jan 26, 2024 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. (less)
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Uncertain significance
(Mar 21, 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: SCV004208099.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090380.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005191524.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
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Uncertain significance
(Apr 02, 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: SCV000149101.20
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 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 leukemia, breast cancer, and Lynch-syndrome associated cancers and/or polyps but also in healthy controls (PMID: 17623063, 19781682, 25980754, 26580448, 26976419, 28652578, 28779002, 29458332, 30374176, 33471991); This variant is associated with the following publications: (PMID: 19781682, 26976419, 28779002, 25980754, 17623063, 29458332, 30374176, 26580448, 28652578, 33436325, 35098669, 33471991) (less)
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Uncertain significance
(Mar 10, 2022)
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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: SCV000611362.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
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Likely benign
(May 17, 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: SCV005083986.1
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
(Aug 19, 2024)
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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: SCV000694278.5
First in ClinVar: Mar 17, 2018 Last updated: Oct 26, 2024 |
Comment:
Variant summary: ATM c.4375G>A (p.Gly1459Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ATM c.4375G>A (p.Gly1459Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 256006 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.1e-05 vs 0.001), allowing no conclusion about variant significance. c.4375G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast/colorectal/pediatric and other cancers (example, Edvardsen_2007, Tung_2016, Yurgelun_2015, Dominguez-Valentin_2018, Zhang_2015, Tsai_2019) but also in controls (example, Tavtigian_2009, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 variant not specified, Tsai_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29458332, 17623063, 19781682, 30374176, 26976419, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 127387). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 16, 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: SCV001462322.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Molecular characteristics of young-onset colorectal cancer in Vietnamese patients. | Do MD | Asia-Pacific journal of clinical oncology | 2022 | PMID: 35098669 |
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 |
Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. | Karlsson Q | European urology oncology | 2021 | PMID: 33436325 |
Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors. | Akhavanfard S | Nature communications | 2020 | PMID: 32371905 |
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
Identification of genetic variants for clinical management of familial colorectal tumors. | Dominguez-Valentin M | BMC medical genetics | 2018 | PMID: 29458332 |
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
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 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
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, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. | Tavtigian SV | American journal of human genetics | 2009 | PMID: 19781682 |
Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. | Edvardsen H | Radiation oncology (London, England) | 2007 | PMID: 17623063 |
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Text-mined citations for rs145667735 ...
HelpRecord last updated Nov 03, 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.