Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 397/277154 (1 homozygote) control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002368 (300/126680). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected BrC pts, along with multiple somatic occurrences in MCL and CLL pts. Skowronska_2012 suggestions, biallelic ATM inactivation in CLL patients was associated with disease progression and reduced survival. However, the variant has been reported to co-occur with a BRCA1 variant, although the exact variant was not indicated (Thorstenson_2003). In addition, two internal LCA samples report the variant to co-occur with a pathogenic ATM variant, c.6095G>A (p.Arg20232Lys) and BRCA1 variant, c.1326T>A (p.Cys442X). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Taken together, this variant is classified as benign.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.6067G>A (p.Gly2023Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(33)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(6); Benign(5); Likely benign(14)
Uncertain significance(6); Benign(5); Likely benign(14)
33
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.6067G>A (p.Gly2023Arg)
Variation ID: 127416 Accession: VCV000127416.78
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108315883 (GRCh38) [ NCBI UCSC ] 11: 108186610 (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 Jun 9, 2014 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.6067G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Gly2023Arg missense NM_000051.2:c.6067G>A NM_001330368.2:c.641-6812C>T intron variant NM_001351110.2:c.*39-6812C>T intron variant NM_001351834.2:c.6067G>A NP_001338763.1:p.Gly2023Arg missense NC_000011.10:g.108315883G>A NC_000011.9:g.108186610G>A NG_009830.1:g.98052G>A NG_054724.1:g.158950C>T LRG_135:g.98052G>A LRG_135t1:c.6067G>A LRG_135p1:p.Gly2023Arg Q13315:p.Gly2023Arg - Protein change
- G2023R
- Other names
-
p.G2023R:GGA>AGA
NP_000042.3:p.Gly2023Arg
- Canonical SPDI
- NC_000011.10:108315882:G:A
-
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.
-
0.00120 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00120
The Genome Aggregation Database (gnomAD) 0.00124
Trans-Omics for Precision Medicine (TOPMed) 0.00132
The Genome Aggregation Database (gnomAD), exomes 0.00143
Exome Aggregation Consortium (ExAC) 0.00157
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00231
- 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 |
10852 | 17462 | |
| C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6592 |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Feb 1, 2024 | RCV000122864.39 | |
| Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000120151.27 | |
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Jul 8, 2020 | RCV000115221.28 | |
| Conflicting interpretations of pathogenicity (11) |
criteria provided, conflicting classifications
|
Aug 1, 2024 | RCV000513642.52 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 30, 2024 | RCV001253480.13 | |
| Likely benign (1) |
no assertion criteria provided
|
- | RCV001356569.9 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 30, 2023 | RCV001798320.11 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV002225322.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 19, 2022 | RCV002225321.9 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000301678.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Benign
(Aug 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694314.1
First in ClinVar: Oct 30, 2017 Last updated: Oct 30, 2017 |
Comment:
Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this … (more)
Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 397/277154 (1 homozygote) control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002368 (300/126680). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected BrC pts, along with multiple somatic occurrences in MCL and CLL pts. Skowronska_2012 suggestions, biallelic ATM inactivation in CLL patients was associated with disease progression and reduced survival. However, the variant has been reported to co-occur with a BRCA1 variant, although the exact variant was not indicated (Thorstenson_2003). In addition, two internal LCA samples report the variant to co-occur with a pathogenic ATM variant, c.6095G>A (p.Arg20232Lys) and BRCA1 variant, c.1326T>A (p.Cys442X). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Taken together, this variant is classified as benign. (less)
|
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001263992.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Dec 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429203.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
|
|
|
Likely benign
(Dec 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000840948.2
First in ClinVar: May 30, 2018 Last updated: Jan 26, 2021 |
|
|
|
Likely benign
(Jul 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001781325.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Sex: mixed
|
|
|
Benign
(Jul 08, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537561.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Likely benign
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149130.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, … (more)
This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, 21787400, 19781682, 24728327, 25624042, 26898890, 27664052, 25980754, 24584352, 27150160, 26483394, 26822149, 27882345, 25625042, 27498913, 28608266, 29678143, 23555315, 26822949, 27621404, 28779002, 30197789, 31108397, 30309722, 31159747, 30303537, 32854451) (less)
|
|
|
Benign
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV000838565.3
First in ClinVar: Oct 10, 2018 Last updated: Aug 25, 2023 |
|
|
|
Likely benign
(Mar 30, 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: SCV002042698.2
First in ClinVar: Jan 03, 2022 Last updated: Feb 04, 2024 |
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166122.14
First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Jul 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000183877.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Likely benign
(May 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV005084010.1
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)
|
|
|
Likely benign
(Jun 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199614.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821865.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
|
Uncertain significance
(Jun 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no, yes
Allele origin:
germline
|
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Accession: SCV001911470.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
Comment:
The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 … (more)
The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 (0.232%, 274/118,126 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026). (less)
Observation 1:
Clinical Features:
No cancer (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
Observation 2:
Clinical Features:
No cancer (present)
Indication for testing: Lung cancer susceptibility
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 3:
Clinical Features:
Múltiple Leiomyomas (present)
Indication for testing: Hereditary leiomyomatosis and renal cell cancer
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous pathogenic variant in FH
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 4:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 5:
Clinical Features:
Ovarian serous tumor (present)
Indication for testing: Familial ovarian cancer
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 6:
Clinical Features:
Breast carcinoma (present) , Bilateral breast cancer (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 7:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 8:
Clinical Features:
Ovarian serous tumor (present)
Indication for testing: Familial ovarian cancer
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 9:
Clinical Features:
Prostate cancer (present) , Colorectal polyposis (present)
Indication for testing: Adenomatous colonic polyposis
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 10:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to, Li-Fraumeni syndrome
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 11:
Clinical Features:
Breast carcinoma (present) , Colorectal cancer (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 12:
Clinical Features:
Ovarian cancer (present)
Indication for testing: Breast and Ovarian Cancer Susceptibility
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous pathogenic variant in BRCA1
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 13:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous likely pathogenic variant in CHEK2
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 14:
Clinical Features:
Bilateral breast cancer (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 15:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 16:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous pathogenic variant in BRCA2
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 17:
Clinical Features:
Bilateral breast cancer (present) , Colorectal cancer (present)
Indication for testing: Breast and Ovarian Cancer Susceptibility
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Familial Cancer Clinical Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Observation 18:
Clinical Features:
Colorectal cancer (present)
Indication for testing: Hereditary nonpolyposis colon cancer
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Comment on evidence:
Carrier of an heterozygous pathogenic variant in MLH1
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
Observation 19:
Clinical Features:
Colorectal cancer (present) , Colorectal cancer (present)
Indication for testing: Hereditary nonpolyposis colon cancer
Zygosity: Single Heterozygote
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
|
|
|
Likely benign
(Dec 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070957.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
|
Uncertain significance
(Apr 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002504743.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Number of individuals with the variant: 2
Geographic origin: South Africa
|
|
|
Likely benign
(Feb 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000687670.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
|
Likely benign
(Oct 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800554.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
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Likely benign
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010799.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely benign
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469357.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
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Uncertain significance
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713581.3
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
BS1
Number of individuals with the variant: 122
|
|
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Likely benign
(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: SCV002760723.5
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
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Likely benign
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608617.31
First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024 |
Comment:
ATM: BS1:Supporting
Number of individuals with the variant: 34
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Likely benign
(Apr 18, 2020)
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no assertion criteria provided
Method: clinical testing
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Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001452119.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551777.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast … (more)
The ATM p.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast cancer and was identified in 2 of 1602 chromosomes (frequency: 0.001) from healthy individuals (Broeks 2008, Gronbaek 2002, Mangone 2015, Paglia 2010, Podralska 2018, Skowronska 2012, Thorstenson 2003, Yurgelun 2015, Balmana 2016, Tung 2016). The variant was also identified in dbSNP (ID: rs11212587) as "With other allele", ClinVar (classified as benign by two clinical laboratories; as likely benign by Invitae, Ambry Genetics and three other submitters; as uncertain significance by one submitter), Cosmic (3x in Large intestine, or Haematopoietic and lymphoid tissue), MutDB, and in LOVD 3.0 (3x) databases. The variant was not identified in COGR. The variant was identified in control databases in 397 of 277154 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24034 chromosomes (freq: 0.0004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 36 of 34418 chromosomes (freq: 0.001), European in 300 of 126680 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), East Asian in 1 of 18852 chromosomes (freq: 0.00005), Finnish in 22 of 25778 chromosomes (freq: 0.0009), and South Asian in 20 of 30780 chromosomes (freq: 0.0007). The p.Gly2023 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In silico analysis predicted the variant induces or contributes to increased exon skipping (Caminsky 2016). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
Number of individuals with the variant: 1
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|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971707.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Mar 16, 2018)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000805219.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Tip-toe gait
Affected status: yes
Allele origin:
germline
|
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV002504684.2
First in ClinVar: Apr 30, 2022 Last updated: Jun 09, 2024 |
Comment:
Gait disorder
Clinical Features:
Pes cavus (present) , Clinodactyly (present) , Brachydactyly (present)
Age: 0-9 years
Sex: female
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|
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084292.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
|
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not provided
(-)
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no classification provided
Method: phenotyping only
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Brain Gene Registry
Accession: SCV003931264.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Variant classified as Uncertain significance and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided … (more)
Variant classified as Uncertain significance and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Recurrent streptococcal infections (present) , Delayed speech and language development (present) , Intellectual disability (present) , Abnormal facial shape (present)
Indication for testing: Diagnostic
Zygosity: Single Heterozygote
Age: 10-19 years
Sex: male
Method: Exome Sequencing
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-02-03
Testing laboratory interpretation: Uncertain significance
|
|
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228873.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 02-18-2016 by Lab GenPath. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 02-18-2016 by Lab GenPath. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Presymptomatic
Zygosity: Single Heterozygote
Age: 40-49 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: GenPath
Date variant was reported to submitter: 2016-02-18
Testing laboratory interpretation: Uncertain significance
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Comment:
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, 21787400, 19781682, 24728327, 25624042, 26898890, 27664052, 25980754, 24584352, 27150160, 26483394, 26822149, 27882345, 25625042, 27498913, 28608266, 29678143, 23555315, 26822949, 27621404, 28779002, 30197789, 31108397, 30309722, 31159747, 30303537, 32854451)
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 variants in this gene [PMID: 25085752].
Comment:
The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 (0.232%, 274/118,126 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
Comment:
BS1
Comment:
ATM: BS1:Supporting
Comment:
The ATM p.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast cancer and was identified in 2 of 1602 chromosomes (frequency: 0.001) from healthy individuals (Broeks 2008, Gronbaek 2002, Mangone 2015, Paglia 2010, Podralska 2018, Skowronska 2012, Thorstenson 2003, Yurgelun 2015, Balmana 2016, Tung 2016). The variant was also identified in dbSNP (ID: rs11212587) as "With other allele", ClinVar (classified as benign by two clinical laboratories; as likely benign by Invitae, Ambry Genetics and three other submitters; as uncertain significance by one submitter), Cosmic (3x in Large intestine, or Haematopoietic and lymphoid tissue), MutDB, and in LOVD 3.0 (3x) databases. The variant was not identified in COGR. The variant was identified in control databases in 397 of 277154 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24034 chromosomes (freq: 0.0004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 36 of 34418 chromosomes (freq: 0.001), European in 300 of 126680 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), East Asian in 1 of 18852 chromosomes (freq: 0.00005), Finnish in 22 of 25778 chromosomes (freq: 0.0009), and South Asian in 20 of 30780 chromosomes (freq: 0.0007). The p.Gly2023 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In silico analysis predicted the variant induces or contributes to increased exon skipping (Caminsky 2016). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Comment:
Gait disorder
Comment:
Variant classified as Uncertain significance and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Comment:
Variant interpreted as Uncertain significance and reported on 02-18-2016 by Lab GenPath. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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. |
Comment:
Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 397/277154 (1 homozygote) control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002368 (300/126680). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected BrC pts, along with multiple somatic occurrences in MCL and CLL pts. Skowronska_2012 suggestions, biallelic ATM inactivation in CLL patients was associated with disease progression and reduced survival. However, the variant has been reported to co-occur with a BRCA1 variant, although the exact variant was not indicated (Thorstenson_2003). In addition, two internal LCA samples report the variant to co-occur with a pathogenic ATM variant, c.6095G>A (p.Arg20232Lys) and BRCA1 variant, c.1326T>A (p.Cys442X). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Taken together, this variant is classified as benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, 21787400, 19781682, 24728327, 25624042, 26898890, 27664052, 25980754, 24584352, 27150160, 26483394, 26822149, 27882345, 25625042, 27498913, 28608266, 29678143, 23555315, 26822949, 27621404, 28779002, 30197789, 31108397, 30309722, 31159747, 30303537, 32854451)
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 variants in this gene [PMID: 25085752].
Comment:
The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 (0.232%, 274/118,126 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
Comment:
BS1
Comment:
ATM: BS1:Supporting
Comment:
The ATM p.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast cancer and was identified in 2 of 1602 chromosomes (frequency: 0.001) from healthy individuals (Broeks 2008, Gronbaek 2002, Mangone 2015, Paglia 2010, Podralska 2018, Skowronska 2012, Thorstenson 2003, Yurgelun 2015, Balmana 2016, Tung 2016). The variant was also identified in dbSNP (ID: rs11212587) as "With other allele", ClinVar (classified as benign by two clinical laboratories; as likely benign by Invitae, Ambry Genetics and three other submitters; as uncertain significance by one submitter), Cosmic (3x in Large intestine, or Haematopoietic and lymphoid tissue), MutDB, and in LOVD 3.0 (3x) databases. The variant was not identified in COGR. The variant was identified in control databases in 397 of 277154 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24034 chromosomes (freq: 0.0004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 36 of 34418 chromosomes (freq: 0.001), European in 300 of 126680 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), East Asian in 1 of 18852 chromosomes (freq: 0.00005), Finnish in 22 of 25778 chromosomes (freq: 0.0009), and South Asian in 20 of 30780 chromosomes (freq: 0.0007). The p.Gly2023 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In silico analysis predicted the variant induces or contributes to increased exon skipping (Caminsky 2016). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Comment:
Gait disorder
Comment:
Variant classified as Uncertain significance and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Comment:
Variant interpreted as Uncertain significance and reported on 02-18-2016 by Lab GenPath. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly. | Pomarino D | Global medical genetics | 2023 | PMID: 37091313 |
| Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
| Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance. | Castillo-Guardiola V | European journal of medical genetics | 2022 | PMID: 35245693 |
| A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
| Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2. | Fanale D | Cancers | 2020 | PMID: 32854451 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| 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 |
| Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population. | Podralska M | BMC cancer | 2018 | PMID: 29678143 |
| Clinical interpretation of pathogenic ATM and CHEK2 variants on multigene panel tests: navigating moderate risk. | West AH | Familial cancer | 2018 | PMID: 29445900 |
| Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families. | Dominguez-Valentin M | Familial cancer | 2018 | PMID: 28608266 |
| Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia. | Carranza D | Neuromolecular medicine | 2017 | PMID: 27664052 |
| Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing. | Balmaña J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 27621404 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| 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 |
| Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients. | Lhota F | Clinical genetics | 2016 | PMID: 26822949 |
| Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
| Detection of novel germline mutations for breast cancer in non-BRCA1/2 families. | Aloraifi F | The FEBS journal | 2015 | PMID: 26094658 |
| Comprehensive Analysis of Disease-Related Genes in Chronic Lymphocytic Leukemia by Multiplex PCR-Based Next Generation Sequencing. | Vollbrecht C | PloS one | 2015 | PMID: 26053404 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| ATM gene mutations in sporadic breast cancer patients from Brazil. | Mangone FR | SpringerPlus | 2015 | PMID: 25625042 |
| 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 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
| Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. | Skowronska A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 23091097 |
| Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. | George Priya Doss C | PloS one | 2012 | PMID: 22529920 |
| ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. | Skowronska A | Haematologica | 2012 | PMID: 21933854 |
| ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy. | Paglia LL | Breast cancer research and treatment | 2010 | PMID: 19404735 |
| Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. | Tavtigian SV | American journal of human genetics | 2009 | PMID: 19781682 |
| The spectrum of ATM missense variants and their contribution to contralateral breast cancer. | Broeks A | Breast cancer research and treatment | 2008 | PMID: 17393301 |
| Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. | Austen B | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2007 | PMID: 17968022 |
| Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. | Greiner TC | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16461462 |
| Contributions of ATM mutations to familial breast and ovarian cancer. | Thorstenson YR | Cancer research | 2003 | PMID: 12810666 |
| ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma. | Grønbaek K | Blood | 2002 | PMID: 12149228 |
| Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. | Teraoka SN | Cancer | 2001 | PMID: 11505391 |
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Text-mined citations for rs11212587 ...
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Record last updated Dec 07, 2024
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