The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI greater than or equal to 1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)
Variation ID: 3023 Accession: VCV000003023.71
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108329202 (GRCh38) [ NCBI UCSC ] 11: 108199929 (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 Sep 29, 2015 Jan 13, 2025 Mar 9, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.7271T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Val2424Gly missense NM_001330368.2:c.641-20131A>C intron variant NM_001351110.2:c.*38+6018A>C intron variant NM_001351834.2:c.7271T>G NP_001338763.1:p.Val2424Gly missense NC_000011.10:g.108329202T>G NC_000011.9:g.108199929T>G NG_009830.1:g.111371T>G NG_054724.1:g.145631A>C LRG_135:g.111371T>G LRG_135t1:c.7271T>G LRG_135p1:p.Val2424Gly Q13315:p.Val2424Gly - Protein change
- V2424G
- Other names
-
p.V2424G:GTA>GGA
NM_000051.3(ATM):c.7271T>G
- Canonical SPDI
- NC_000011.10:108329201:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
- 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 |
10978 | 17671 | |
| C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6675 |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Nov 1, 2006 | RCV000003159.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 1, 2006 | RCV000003160.15 | |
| risk factor (1) |
no assertion criteria provided
|
Nov 1, 2006 | RCV000003161.13 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 4, 2024 | RCV000115244.26 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000168223.44 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2022 | RCV000212060.31 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2016 | RCV000417259.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2017 | RCV000515429.10 | |
| Pathogenic (5) |
reviewed by expert panel
|
Mar 9, 2022 | RCV000709707.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 5, 2022 | RCV003149562.10 | |
|
ATM-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 11, 2024 | RCV004739284.1 |
|
Inherited breast cancer and ovarian cancer
|
Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2024 | RCV004584137.1 |
|
NICE approved PARP inhibitor treatment
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 24, 2024 | RCV004584175.1 |
| click to load more click to collapse | ||||
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 09, 2022)
|
reviewed by expert panel
Method: curation
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV002499282.1 First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the … (more)
The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI greater than or equal to 1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (less)
|
|
|
Pathogenic
(Sep 22, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Study: Adult_WES
Accession: SCV000245452.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
This variant has been previously reported as disease-causing and was found twice in our laboratory in affected individuals who carried second pathogenic variants in the … (more)
This variant has been previously reported as disease-causing and was found twice in our laboratory in affected individuals who carried second pathogenic variants in the gene. (less)
Number of individuals with the variant: 2
Zygosity: Homozygote, Single Heterozygote, Compound Heterozygote
Age: 3-27 years
Sex: mixed
|
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611166.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
|
Pathogenic
(Oct 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713585.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4, PM2, PM3, PP1, PP3, PP5
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762230.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Cerebellar ataxia (present) , Dystonic disorder (present) , Elevated circulating alpha-fetoprotein concentration (present)
Sex: male
|
|
|
Pathogenic
(Feb 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149153.15
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
Case-control studies suggest this variant is associated with breast cancer and confers a higher risk than other ATM variants (Stankovic 1998, Chenevix-Trench 2002, Bernstein 2006, … (more)
Case-control studies suggest this variant is associated with breast cancer and confers a higher risk than other ATM variants (Stankovic 1998, Chenevix-Trench 2002, Bernstein 2006, Goldgar 2011, van Os 2016, Southey 2016, Thompson 2016, Decker 2017); Published functional studies demonstrate a damaging effect: cells heterozygous for this variant demonstrate radiosensitivity and decreased kinase activity (Stewart 2001, Chenevix-Trench 2002, Barone 2009, Mitui 2009, Taylor 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Huang 2015, Hart 2016, Southey 2016, Thompson 2016, Decker 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 26506520, 27595995, 28580595, 27913932, 28452373, 25186627, 29915382, 30549301, 8755918, 16958054, 21787400, 17001622, 24733792, 15928302, 9463314, 24763289, 18634022, 9288106, 22529920, 19781682, 24088041, 11382771, 26786923, 19431188, 26662178, 11830610, 26633545, 26985847, 25980754, 27273131, 14871810, 27528516, 26681312, 28779002, 28454591, 27988859, 28643015, 28840378, 28691344, 29034753, 27798748, 28821472, 28390840, 28439798, 29719442, 29271107, 29665859, 29661970, 29422015, 29341116, 29555025, 27084275, 29506079, 25040471, 18575927, 30197789, 27978560, 31447099) (less)
|
|
|
Pathogenic
(Apr 10, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537398.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.7271T>G (p.V2424G) variant has been reported in multiple families affected with ataxia-telangiectasia (A-T), breast cancer, and gastric cancer (PMID: 9463314, 8755918, 21787400, 24733792, … (more)
The ATM c.7271T>G (p.V2424G) variant has been reported in multiple families affected with ataxia-telangiectasia (A-T), breast cancer, and gastric cancer (PMID: 9463314, 8755918, 21787400, 24733792, 26506520, 17001622). A large case-control study found the variant to be associated with breast cancer OR 11.0 (95% CI 1.42 to 85.7, p=0.0012) with a 52% cumulative risk of breast cancer at age of 70 (PMID: 27595995). A functional study demonstrated that the variant impairs ATM kinase activity (PMID: 18634022). It was observed in 11/128854 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 3023). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Pathogenic
(Apr 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761739.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Mar 11, 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: SCV000602560.4
First in ClinVar: Sep 30, 2017 Last updated: Mar 04, 2023 |
Comment:
The ATM c.7271T>G; p.Val2424Gly variant (rs28904921) is associated with an increased risk for breast and other cancers (Goldgar 2011, Kurian 2014, Stankovic 1998, Tavtigian 2009, … (more)
The ATM c.7271T>G; p.Val2424Gly variant (rs28904921) is associated with an increased risk for breast and other cancers (Goldgar 2011, Kurian 2014, Stankovic 1998, Tavtigian 2009, Yurgelun 2015). It is also reported in association with autosomal recessive ataxia telangiectasia in both a homozygous state and in a compound heterozygous state with other ATM variants. (McConville 1996, Stankovic 1998). The p.Val2424Gly variant does not alter the abundance of the ATM protein but several studies have shown that it impairs ATM kinase activity and DNA repair (Barone 2009, Mitui 2009, Stankovic 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3023). It is found in the general population with an overall allele frequency of 0.004% (12/282354 alleles) in the Genome Aggregation Database. The valine at codon 2424 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-1230. Goldgar DE et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-2009. McConville CM et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996 Aug;59(2):320-30 Mitui M et al. Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat. 2009 Jan;30(1):12-21 Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-345. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-446. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. (less)
|
|
|
Pathogenic
(Apr 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021984.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292134.4
First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with glycine at codon 2424 in the FAT domain of the ATM protein. Computational prediction suggests that this variant may … (more)
This missense variant replaces valine with glycine at codon 2424 in the FAT domain of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a significantly decreased ATM kinase activity (PMID: 11382771, 11830610, 18634022). This variant has been reported in over 50 individuals affected with breast cancer (PMID: 9463314, 11830610, 16958054, 21787400, 24733792, 25186627, 26681312, 27595995, 27798748, 28779002). Several large breast cancer case-control studies reported this variant to confer increased risk of the disease (PMID: 27595995, 33471991, 33509806), comparable to BRCA1 and BRCA2 pathogenic mutations (PMID: 11830610, 16958054, 26662178). This variant has been observed in multiple families affected with attenuated ataxia-telangiectasia in homozygous state or compound heterozygous state with pathogenic truncation variants (PMID: 8755918, 9463314, 18575927, 27528516, 30549301, 32748564). This variant has been identified in 12/282354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218891.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2424 of the ATM protein (p.Val2424Gly). … (more)
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2424 of the ATM protein (p.Val2424Gly). This variant is present in population databases (rs28904921, gnomAD 0.01%). This missense change has been observed in individual(s) with gastric cancer, breast cancer, autosomal recessive ataxia-telangiectasia (PMID: 8755918, 9463314, 11830610, 16958054, 18575927, 19781682, 21787400, 24733792, 26506520). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3023). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 11382771, 11830610, 18634022, 19431188). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203716.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557567.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (AT; MIM#208900) and cancer susceptibility (MIM#114480). (I) 0106 - This gene is associated with autosomal recessive ataxia-telangiectasia. However, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastic, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMID: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (12 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated FAT domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals in a homozygous or compound heterozygous state with ataxia-telangiectasia, with a predominantly mild form of disease (ClinVar, PMID: 9463314, 30549301). This variant has also been reported to cause a significantly increased risk of breast cancer in heterozygous females (ClinVar, PMID: 27595995). Lifetime risk of breast cancer in women heterozygous for this variant is 52-69% (PMID: 16958054, 26662178). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on patient cells and transfected human cell lines show that this variant results in protein expression similar to wild-type, but significantly reduced kinase activity (PMID: 11382771, 18634022). This variant may act in a dominant negative manner (PMID: 11830610, 17001622). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jul 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000172910.10
First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025 |
Comment:
The p.V2424G pathogenic mutation (also known as c.7271T>G), located in coding exon 48 of the ATM gene, results from a T to G substitution at … (more)
The p.V2424G pathogenic mutation (also known as c.7271T>G), located in coding exon 48 of the ATM gene, results from a T to G substitution at nucleotide position 7271. The valine at codon 2424 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with ataxia-telangiectasia (AT) (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Marelli C et al. Hum. Mutat. 2016 Dec;37:1340-1353), colorectal cancer (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471) as well as individuals with personal history of breast cancer (Kurian AW et al. J. Clin. Oncol. 2014 Jul;32:2001-9; Tung N et al. Cancer. 2015 Jan;121:25-33; Southey MC et al. J. Med. Genet. 2016 12;53:800-811; Susswein LR et al. Genet. Med. 2016 08;18:823-32; Moran O et al. Breast Cancer Res. Treat. 2017 01;161:135-142; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This alteration impacts an evolutionarily conserved residue in the 3' FAT functional domain of the ATM protein and has been shown to act in a dominant-negative manner (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Waddell N et al. Genes Chromosomes Cancer. 2006 Dec;45:1169-81). In a large case-control study the p.V2424G pathogenic mutation was shown to be associated with a significantly increased risk for breast cancer (OR=11.0, 95% CI 1.42 to 85.7) (Southey MC et al. J. Med. Genet. 2016 12;53:800-811). Pedigree analyses of numerous p.V2424G-carrier families with multiple cases of breast cancer have produced lifetime cumulative breast cancer risk estimates ranging from 52% to 69% for this specific allele (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Chenevix-Trench G et al. J. Natl. Cancer Inst. 2002 Feb;94:205-15; Bernstein JL et al. Hum. Mutat. 2006 Nov;27:1122-8; Goldgar D et al. Breast Cancer Res. 2011 Jul;13:R73). Functional assays show that this mutation retains some residual kinase activity and has been seen in some patients with a milder AT phenotype (Thompson D et al. J. Natl. Cancer Inst. 2005 Jun;97:813-22; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 27, 2014)
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criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000246619.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Jun 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694344.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
|
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Pathogenic
(Apr 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839881.1
First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018 |
Comment:
This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the … (more)
This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 18634022]. This variant has seen observed at the heterozygous state in at least 24 patients from two cohorts of breast cancer patients [PMID 19781682, 21787400]. Statistical analysis in one cohort estimated the risk factor for breast cancer to be 8.0 for carriers of this variant compared to 4.4 for families carriers of other pathogenic variants. This variant was observed in 3 Europeans (Non Finnish) at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/11-108199929-T-G). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Val2424Gly change to be deleterious. It is thus interpreted as a pathogenic variant. (less)
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Likely pathogenic
(May 16, 2016)
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criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486203.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 28, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Familial breast cancer
Affected status: unknown
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003798999.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PP3, PS3_Moderate, PS4, PM3_Very strong, PP1
Secondary finding: yes
|
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Pathogenic
(Oct 13, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222109.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000085 (11/128854 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000085 (11/128854 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals/families with breast cancer (PMIDs: 32427313 (2020), 27798748 (2017), 25186627 (2015), 24733792 (2014), 16958054 (2006), 16832357 (2006), 17001622 (2006), 14562025 (2003)) as well as individuals with other cancers such as gastric, prostate, or leukemia (PMIDs: 32338768 (2020), 26506520 (2015), 9892178 (1999), 9288106 (1997)). This variant was shown to be strongly associated with breast cancer risk among Caucasian women (PMIDs: 27595995 (2016), 21787400 (2011)), with estimated cumulative breast cancer risk to age 70 years (penetrance) 34-60% (PMIDs: 17001622 (2006), 16958054 (2006), 11830610 (2002)). In addition, this variant has been reported in individuals/families with ataxia-telangiectasia (PMIDs: 30549301 (2019), 18575927 (2008), 9463314 (1998), 8755918 (1996)). Furthermore, experimental studies have demonstrated that this variant results in reduced/null ATM kinase activity (PMID: 18634022 (2009), 11830610 (2002), 11382771 (2001)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 05, 2022)
|
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: SCV003837905.2
First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inherited breast cancer and ovarian cancer
Affected status: yes
Allele origin:
germline
|
NHS Central & South Genomic Laboratory Hub
Accession: SCV005068246.1
First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024 |
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Pathogenic
(Apr 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
NICE approved PARP inhibitor treatment
Affected status: yes
Allele origin:
germline
|
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV005068347.1
First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024 |
Comment:
PS3_Moderate,PS4,PM3_Strong,PP3
|
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Pathogenic
(Nov 01, 2006)
|
no assertion criteria provided
Method: literature only
|
ATAXIA-TELANGIECTASIA VARIANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023317.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016 |
Comment on evidence:
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') … (more)
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') (AT; 208900). The transversion results in a val2424-to-gly (V2424G) substitution. They also reported another point mutation (F2827C; 607585.0006). The authors noted that point mutations are uncommon in AT. In a sporadic case of T-cell prolymphocytic leukemia (TPLL), Vorechovsky et al. (1997) observed this same mutation in tumor tissue. No wildtype allele was demonstrable in tumor DNA. Material was not available to permit determination of whether the mutation was present in the germline. Stankovic et al. (1998) observed 2 families in which members affected with a milder clinical and cellular phenotype of AT shared a 7271T-G transversion in the ATM gene and a common haplotype. The 7271T-G mutation was predicted to produce a V2424G substitution. One family, in which the mutation was present in homozygous state, contained the oldest patients in the British Isles with demonstrable AT, including 1 patient in his seventh decade, possibly the oldest AT patient reported. Furthermore, 1 affected female, 50 years old at the time of report, had an unaffected son. Three members of a sibship of 4 had long-standing ataxia. Their parents were first cousins and originated from Orkney, in the north of Scotland. The proband, her older sister with AT, and her mother had breast cancer. The affected individuals had minimal telangiectasia and no obvious increased tendency toward infections, except for recurrent urinary tract infections in the brother of the proband. The second family had the 7271T-G transversion in compound heterozygous state with a 3910del7nt mutation. The mutation was predicted to cause premature termination of the ATM protein, but no truncated ATM protein was detected. There were 2 affected brothers, aged 16 and 28 years, whose age at onset of ataxia was 8 and 4 years, respectively. Two of 3 paternal aunts had breast cancer, one at age 50 years and the other at age 55 years. In a population-based study, Bernstein et al. (2006) identified a heterozygous 7271T-G transversion in 7 (0.2%) of 3,743 patients with breast cancer (114480) and none of 1,268 controls. Among the patients, the mutant allele was more prevalent in women with an affected mother (odds ratio of 5.5) and delayed child-bearing (odds ratio of 5.1). The estimated cumulative risk for breast cancer in carriers to age 70 years (penetrance) was 52%. (less)
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Pathogenic
(Nov 01, 2006)
|
no assertion criteria provided
Method: literature only
|
T-CELL PROLYMPHOCYTIC LEUKEMIA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000023318.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016 |
Comment on evidence:
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') … (more)
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') (AT; 208900). The transversion results in a val2424-to-gly (V2424G) substitution. They also reported another point mutation (F2827C; 607585.0006). The authors noted that point mutations are uncommon in AT. In a sporadic case of T-cell prolymphocytic leukemia (TPLL), Vorechovsky et al. (1997) observed this same mutation in tumor tissue. No wildtype allele was demonstrable in tumor DNA. Material was not available to permit determination of whether the mutation was present in the germline. Stankovic et al. (1998) observed 2 families in which members affected with a milder clinical and cellular phenotype of AT shared a 7271T-G transversion in the ATM gene and a common haplotype. The 7271T-G mutation was predicted to produce a V2424G substitution. One family, in which the mutation was present in homozygous state, contained the oldest patients in the British Isles with demonstrable AT, including 1 patient in his seventh decade, possibly the oldest AT patient reported. Furthermore, 1 affected female, 50 years old at the time of report, had an unaffected son. Three members of a sibship of 4 had long-standing ataxia. Their parents were first cousins and originated from Orkney, in the north of Scotland. The proband, her older sister with AT, and her mother had breast cancer. The affected individuals had minimal telangiectasia and no obvious increased tendency toward infections, except for recurrent urinary tract infections in the brother of the proband. The second family had the 7271T-G transversion in compound heterozygous state with a 3910del7nt mutation. The mutation was predicted to cause premature termination of the ATM protein, but no truncated ATM protein was detected. There were 2 affected brothers, aged 16 and 28 years, whose age at onset of ataxia was 8 and 4 years, respectively. Two of 3 paternal aunts had breast cancer, one at age 50 years and the other at age 55 years. In a population-based study, Bernstein et al. (2006) identified a heterozygous 7271T-G transversion in 7 (0.2%) of 3,743 patients with breast cancer (114480) and none of 1,268 controls. Among the patients, the mutant allele was more prevalent in women with an affected mother (odds ratio of 5.5) and delayed child-bearing (odds ratio of 5.1). The estimated cumulative risk for breast cancer in carriers to age 70 years (penetrance) was 52%. (less)
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risk factor
(Nov 01, 2006)
|
no assertion criteria provided
Method: literature only
|
BREAST CANCER, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023319.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016 |
Comment on evidence:
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') … (more)
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') (AT; 208900). The transversion results in a val2424-to-gly (V2424G) substitution. They also reported another point mutation (F2827C; 607585.0006). The authors noted that point mutations are uncommon in AT. In a sporadic case of T-cell prolymphocytic leukemia (TPLL), Vorechovsky et al. (1997) observed this same mutation in tumor tissue. No wildtype allele was demonstrable in tumor DNA. Material was not available to permit determination of whether the mutation was present in the germline. Stankovic et al. (1998) observed 2 families in which members affected with a milder clinical and cellular phenotype of AT shared a 7271T-G transversion in the ATM gene and a common haplotype. The 7271T-G mutation was predicted to produce a V2424G substitution. One family, in which the mutation was present in homozygous state, contained the oldest patients in the British Isles with demonstrable AT, including 1 patient in his seventh decade, possibly the oldest AT patient reported. Furthermore, 1 affected female, 50 years old at the time of report, had an unaffected son. Three members of a sibship of 4 had long-standing ataxia. Their parents were first cousins and originated from Orkney, in the north of Scotland. The proband, her older sister with AT, and her mother had breast cancer. The affected individuals had minimal telangiectasia and no obvious increased tendency toward infections, except for recurrent urinary tract infections in the brother of the proband. The second family had the 7271T-G transversion in compound heterozygous state with a 3910del7nt mutation. The mutation was predicted to cause premature termination of the ATM protein, but no truncated ATM protein was detected. There were 2 affected brothers, aged 16 and 28 years, whose age at onset of ataxia was 8 and 4 years, respectively. Two of 3 paternal aunts had breast cancer, one at age 50 years and the other at age 55 years. In a population-based study, Bernstein et al. (2006) identified a heterozygous 7271T-G transversion in 7 (0.2%) of 3,743 patients with breast cancer (114480) and none of 1,268 controls. Among the patients, the mutant allele was more prevalent in women with an affected mother (odds ratio of 5.5) and delayed child-bearing (odds ratio of 5.1). The estimated cumulative risk for breast cancer in carriers to age 70 years (penetrance) was 52%. (less)
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Pathogenic
(Aug 01, 2016)
|
no assertion criteria provided
Method: research
|
Breast cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000503552.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Found in a male patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with bilateral … (more)
Found in a male patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with bilateral breast cancer diagnosed at age 88 and 93. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001554125.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Val2424Gly variant was identified in 20 of 14588 proband chromosomes (frequency: 0.0013) from individuals or families with contralateral and bilateral breast cancers (Bernstein … (more)
The ATM p.Val2424Gly variant was identified in 20 of 14588 proband chromosomes (frequency: 0.0013) from individuals or families with contralateral and bilateral breast cancers (Bernstein 2003, Bernstein 2010, Chenevix-Trench 2002, Goldgar 2011, Waddell 2006). The variant was also identified in dbSNP (ID: rs28904921) as “with pathogenic allele”, in the ClinVar database (as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 additional clinical laboratories, and as likely pathogenic by Counsyl), in the Cosmic database (2x as pathogenic), and in the LOVD 3.0 database (6x as pathogenic). The variant was not identified in the COGR or in the MutDB databases. The variant was also identified in control databases including the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles and in 14 of 276788 chromosomes at a frequency of 0.00005 in the Genome Aggregation Database (Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34412 chromosomes (freq: 0.00003), and European Non-Finnish in 13 of 126414 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vivo analyses of cell lines established from individuals heterozygous for the c.7271T>G variant suggest that this ATM variant acts in a dominant negative manner so that the wild-type enzyme is unable to function normally in the presence of the mutant protein. Results reveal that the mutant ATM protein from the c.7271T>G heterozygotes is stable but intrinsically defective as a kinase. It appears that, in cells with these mutant ATM alleles, p53 phosphorylation and stabilization are reduced, which presumably decreases the effectiveness of the cell cycle checkpoint (Chenevix-Trench 2002). In another study, the c.7271T>G variant was genotyped and modified segregation analysis was used to estimate the breast cancer penetrance. Women carrying the variant, ATM c.7271T>G demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2. Separate analyses of the 15 families carrying the ATM c.7271T>G variant found that this variant increased breast cancer risk by a factor of 8.0 compared with 4.4 for families with other ATM variants (Goldgar 2011). Another study confirmed that the p.Val2424Gly variant confers a moderate risk of breast cancer, with an estimated hazard ratio of 6.1. Furthermore, the study revealed that the V2424 allele was found across seven vertebrate sequences. To elucidate the molecular effects of the ATM 7271T>G variant, a study carried out expression profiling and demonstrated that the ATM 7271T>G variant acts largely as a dominant negative causing differences in expression profiles of many genes (Waddell 2006). The p.Val2424 residue is conserved across mammals and other 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 4 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 this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001962788.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Dec 14, 2020)
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no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002078174.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Jul 11, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ATM-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005346782.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ATM c.7271T>G variant is predicted to result in the amino acid substitution p.Val2424Gly. This variant has been reported in individuals with ataxia telangiectasia (Stankovic … (more)
The ATM c.7271T>G variant is predicted to result in the amino acid substitution p.Val2424Gly. This variant has been reported in individuals with ataxia telangiectasia (Stankovic et al. 1998. PubMed ID: 9463314; McConville et al. 1996. PubMed ID: 8755918), multiple individuals with breast cancer (see for example - Bernstein et al. 2006. PubMed ID: 16958054; Goldgar et al. 2011. PubMed ID: 21787400), and one individual with gastric cancer (Huang et al. 2015. PubMed ID: 26506520). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3023/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954117.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001974891.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Not Provided
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000986703.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as pathogenic and reported on 11/30/2017 by GTR ID Trillium Health Partners. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as pathogenic and reported on 11/30/2017 by GTR ID Trillium Health Partners. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormality of the intestine (present) , Abnormality of thrombocytes (present) , Abnormality of erythrocytes (present) , Abnormality … (more)
Abnormality of vision (present) , Myopia (present) , Abnormality of the intestine (present) , Abnormality of thrombocytes (present) , Abnormality of erythrocytes (present) , Abnormality of leukocytes (present) , Breast carcinoma (present) (less)
Age: 60-69 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: Genetics Laboratory, Trillium Health Partners,Trillium Health Partners, Credit Valley Hospital Site
Date variant was reported to submitter: 2017-11-30
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
This variant has been previously reported as disease-causing and was found twice in our laboratory in affected individuals who carried second pathogenic variants in the gene.
Comment:
PS3, PS4, PM2, PM3, PP1, PP3, PP5
Comment:
Case-control studies suggest this variant is associated with breast cancer and confers a higher risk than other ATM variants (Stankovic 1998, Chenevix-Trench 2002, Bernstein 2006, Goldgar 2011, van Os 2016, Southey 2016, Thompson 2016, Decker 2017); Published functional studies demonstrate a damaging effect: cells heterozygous for this variant demonstrate radiosensitivity and decreased kinase activity (Stewart 2001, Chenevix-Trench 2002, Barone 2009, Mitui 2009, Taylor 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Huang 2015, Hart 2016, Southey 2016, Thompson 2016, Decker 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 26506520, 27595995, 28580595, 27913932, 28452373, 25186627, 29915382, 30549301, 8755918, 16958054, 21787400, 17001622, 24733792, 15928302, 9463314, 24763289, 18634022, 9288106, 22529920, 19781682, 24088041, 11382771, 26786923, 19431188, 26662178, 11830610, 26633545, 26985847, 25980754, 27273131, 14871810, 27528516, 26681312, 28779002, 28454591, 27988859, 28643015, 28840378, 28691344, 29034753, 27798748, 28821472, 28390840, 28439798, 29719442, 29271107, 29665859, 29661970, 29422015, 29341116, 29555025, 27084275, 29506079, 25040471, 18575927, 30197789, 27978560, 31447099)
Comment:
The ATM c.7271T>G; p.Val2424Gly variant (rs28904921) is associated with an increased risk for breast and other cancers (Goldgar 2011, Kurian 2014, Stankovic 1998, Tavtigian 2009, Yurgelun 2015). It is also reported in association with autosomal recessive ataxia telangiectasia in both a homozygous state and in a compound heterozygous state with other ATM variants. (McConville 1996, Stankovic 1998). The p.Val2424Gly variant does not alter the abundance of the ATM protein but several studies have shown that it impairs ATM kinase activity and DNA repair (Barone 2009, Mitui 2009, Stankovic 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3023). It is found in the general population with an overall allele frequency of 0.004% (12/282354 alleles) in the Genome Aggregation Database. The valine at codon 2424 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-1230. Goldgar DE et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-2009. McConville CM et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996 Aug;59(2):320-30 Mitui M et al. Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat. 2009 Jan;30(1):12-21 Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-345. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-446. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.
Comment:
This missense variant replaces valine with glycine at codon 2424 in the FAT domain of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a significantly decreased ATM kinase activity (PMID: 11382771, 11830610, 18634022). This variant has been reported in over 50 individuals affected with breast cancer (PMID: 9463314, 11830610, 16958054, 21787400, 24733792, 25186627, 26681312, 27595995, 27798748, 28779002). Several large breast cancer case-control studies reported this variant to confer increased risk of the disease (PMID: 27595995, 33471991, 33509806), comparable to BRCA1 and BRCA2 pathogenic mutations (PMID: 11830610, 16958054, 26662178). This variant has been observed in multiple families affected with attenuated ataxia-telangiectasia in homozygous state or compound heterozygous state with pathogenic truncation variants (PMID: 8755918, 9463314, 18575927, 27528516, 30549301, 32748564). This variant has been identified in 12/282354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2424 of the ATM protein (p.Val2424Gly). This variant is present in population databases (rs28904921, gnomAD 0.01%). This missense change has been observed in individual(s) with gastric cancer, breast cancer, autosomal recessive ataxia-telangiectasia (PMID: 8755918, 9463314, 11830610, 16958054, 18575927, 19781682, 21787400, 24733792, 26506520). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3023). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 11382771, 11830610, 18634022, 19431188). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (AT; MIM#208900) and cancer susceptibility (MIM#114480). (I) 0106 - This gene is associated with autosomal recessive ataxia-telangiectasia. However, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastic, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMID: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (12 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated FAT domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals in a homozygous or compound heterozygous state with ataxia-telangiectasia, with a predominantly mild form of disease (ClinVar, PMID: 9463314, 30549301). This variant has also been reported to cause a significantly increased risk of breast cancer in heterozygous females (ClinVar, PMID: 27595995). Lifetime risk of breast cancer in women heterozygous for this variant is 52-69% (PMID: 16958054, 26662178). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on patient cells and transfected human cell lines show that this variant results in protein expression similar to wild-type, but significantly reduced kinase activity (PMID: 11382771, 18634022). This variant may act in a dominant negative manner (PMID: 11830610, 17001622). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The p.V2424G pathogenic mutation (also known as c.7271T>G), located in coding exon 48 of the ATM gene, results from a T to G substitution at nucleotide position 7271. The valine at codon 2424 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with ataxia-telangiectasia (AT) (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Marelli C et al. Hum. Mutat. 2016 Dec;37:1340-1353), colorectal cancer (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471) as well as individuals with personal history of breast cancer (Kurian AW et al. J. Clin. Oncol. 2014 Jul;32:2001-9; Tung N et al. Cancer. 2015 Jan;121:25-33; Southey MC et al. J. Med. Genet. 2016 12;53:800-811; Susswein LR et al. Genet. Med. 2016 08;18:823-32; Moran O et al. Breast Cancer Res. Treat. 2017 01;161:135-142; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This alteration impacts an evolutionarily conserved residue in the 3' FAT functional domain of the ATM protein and has been shown to act in a dominant-negative manner (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Waddell N et al. Genes Chromosomes Cancer. 2006 Dec;45:1169-81). In a large case-control study the p.V2424G pathogenic mutation was shown to be associated with a significantly increased risk for breast cancer (OR=11.0, 95% CI 1.42 to 85.7) (Southey MC et al. J. Med. Genet. 2016 12;53:800-811). Pedigree analyses of numerous p.V2424G-carrier families with multiple cases of breast cancer have produced lifetime cumulative breast cancer risk estimates ranging from 52% to 69% for this specific allele (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Chenevix-Trench G et al. J. Natl. Cancer Inst. 2002 Feb;94:205-15; Bernstein JL et al. Hum. Mutat. 2006 Nov;27:1122-8; Goldgar D et al. Breast Cancer Res. 2011 Jul;13:R73). Functional assays show that this mutation retains some residual kinase activity and has been seen in some patients with a milder AT phenotype (Thompson D et al. J. Natl. Cancer Inst. 2005 Jun;97:813-22; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Comment:
This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 18634022]. This variant has seen observed at the heterozygous state in at least 24 patients from two cohorts of breast cancer patients [PMID 19781682, 21787400]. Statistical analysis in one cohort estimated the risk factor for breast cancer to be 8.0 for carriers of this variant compared to 4.4 for families carriers of other pathogenic variants. This variant was observed in 3 Europeans (Non Finnish) at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/11-108199929-T-G). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Val2424Gly change to be deleterious. It is thus interpreted as a pathogenic variant.
Comment:
PP3, PS3_Moderate, PS4, PM3_Very strong, PP1
Comment:
The frequency of this variant in the general population, 0.000085 (11/128854 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals/families with breast cancer (PMIDs: 32427313 (2020), 27798748 (2017), 25186627 (2015), 24733792 (2014), 16958054 (2006), 16832357 (2006), 17001622 (2006), 14562025 (2003)) as well as individuals with other cancers such as gastric, prostate, or leukemia (PMIDs: 32338768 (2020), 26506520 (2015), 9892178 (1999), 9288106 (1997)). This variant was shown to be strongly associated with breast cancer risk among Caucasian women (PMIDs: 27595995 (2016), 21787400 (2011)), with estimated cumulative breast cancer risk to age 70 years (penetrance) 34-60% (PMIDs: 17001622 (2006), 16958054 (2006), 11830610 (2002)). In addition, this variant has been reported in individuals/families with ataxia-telangiectasia (PMIDs: 30549301 (2019), 18575927 (2008), 9463314 (1998), 8755918 (1996)). Furthermore, experimental studies have demonstrated that this variant results in reduced/null ATM kinase activity (PMID: 18634022 (2009), 11830610 (2002), 11382771 (2001)). Based on the available information, this variant is classified as pathogenic.
Comment:
PS3_Moderate,PS4,PM3_Strong,PP3
Comment:
Found in a male patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with bilateral breast cancer diagnosed at age 88 and 93.
Comment:
The ATM p.Val2424Gly variant was identified in 20 of 14588 proband chromosomes (frequency: 0.0013) from individuals or families with contralateral and bilateral breast cancers (Bernstein 2003, Bernstein 2010, Chenevix-Trench 2002, Goldgar 2011, Waddell 2006). The variant was also identified in dbSNP (ID: rs28904921) as “with pathogenic allele”, in the ClinVar database (as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 additional clinical laboratories, and as likely pathogenic by Counsyl), in the Cosmic database (2x as pathogenic), and in the LOVD 3.0 database (6x as pathogenic). The variant was not identified in the COGR or in the MutDB databases. The variant was also identified in control databases including the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles and in 14 of 276788 chromosomes at a frequency of 0.00005 in the Genome Aggregation Database (Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34412 chromosomes (freq: 0.00003), and European Non-Finnish in 13 of 126414 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vivo analyses of cell lines established from individuals heterozygous for the c.7271T>G variant suggest that this ATM variant acts in a dominant negative manner so that the wild-type enzyme is unable to function normally in the presence of the mutant protein. Results reveal that the mutant ATM protein from the c.7271T>G heterozygotes is stable but intrinsically defective as a kinase. It appears that, in cells with these mutant ATM alleles, p53 phosphorylation and stabilization are reduced, which presumably decreases the effectiveness of the cell cycle checkpoint (Chenevix-Trench 2002). In another study, the c.7271T>G variant was genotyped and modified segregation analysis was used to estimate the breast cancer penetrance. Women carrying the variant, ATM c.7271T>G demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2. Separate analyses of the 15 families carrying the ATM c.7271T>G variant found that this variant increased breast cancer risk by a factor of 8.0 compared with 4.4 for families with other ATM variants (Goldgar 2011). Another study confirmed that the p.Val2424Gly variant confers a moderate risk of breast cancer, with an estimated hazard ratio of 6.1. Furthermore, the study revealed that the V2424 allele was found across seven vertebrate sequences. To elucidate the molecular effects of the ATM 7271T>G variant, a study carried out expression profiling and demonstrated that the ATM 7271T>G variant acts largely as a dominant negative causing differences in expression profiles of many genes (Waddell 2006). The p.Val2424 residue is conserved across mammals and other 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 4 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 this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The ATM c.7271T>G variant is predicted to result in the amino acid substitution p.Val2424Gly. This variant has been reported in individuals with ataxia telangiectasia (Stankovic et al. 1998. PubMed ID: 9463314; McConville et al. 1996. PubMed ID: 8755918), multiple individuals with breast cancer (see for example - Bernstein et al. 2006. PubMed ID: 16958054; Goldgar et al. 2011. PubMed ID: 21787400), and one individual with gastric cancer (Huang et al. 2015. PubMed ID: 26506520). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3023/). This variant is interpreted as pathogenic.
Comment:
Variant interpretted as pathogenic and reported on 11/30/2017 by GTR ID Trillium Health Partners. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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:
The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI greater than or equal to 1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Comment:
This variant has been previously reported as disease-causing and was found twice in our laboratory in affected individuals who carried second pathogenic variants in the gene.
Comment:
PS3, PS4, PM2, PM3, PP1, PP3, PP5
Comment:
Case-control studies suggest this variant is associated with breast cancer and confers a higher risk than other ATM variants (Stankovic 1998, Chenevix-Trench 2002, Bernstein 2006, Goldgar 2011, van Os 2016, Southey 2016, Thompson 2016, Decker 2017); Published functional studies demonstrate a damaging effect: cells heterozygous for this variant demonstrate radiosensitivity and decreased kinase activity (Stewart 2001, Chenevix-Trench 2002, Barone 2009, Mitui 2009, Taylor 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Huang 2015, Hart 2016, Southey 2016, Thompson 2016, Decker 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 26506520, 27595995, 28580595, 27913932, 28452373, 25186627, 29915382, 30549301, 8755918, 16958054, 21787400, 17001622, 24733792, 15928302, 9463314, 24763289, 18634022, 9288106, 22529920, 19781682, 24088041, 11382771, 26786923, 19431188, 26662178, 11830610, 26633545, 26985847, 25980754, 27273131, 14871810, 27528516, 26681312, 28779002, 28454591, 27988859, 28643015, 28840378, 28691344, 29034753, 27798748, 28821472, 28390840, 28439798, 29719442, 29271107, 29665859, 29661970, 29422015, 29341116, 29555025, 27084275, 29506079, 25040471, 18575927, 30197789, 27978560, 31447099)
Comment:
The ATM c.7271T>G; p.Val2424Gly variant (rs28904921) is associated with an increased risk for breast and other cancers (Goldgar 2011, Kurian 2014, Stankovic 1998, Tavtigian 2009, Yurgelun 2015). It is also reported in association with autosomal recessive ataxia telangiectasia in both a homozygous state and in a compound heterozygous state with other ATM variants. (McConville 1996, Stankovic 1998). The p.Val2424Gly variant does not alter the abundance of the ATM protein but several studies have shown that it impairs ATM kinase activity and DNA repair (Barone 2009, Mitui 2009, Stankovic 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3023). It is found in the general population with an overall allele frequency of 0.004% (12/282354 alleles) in the Genome Aggregation Database. The valine at codon 2424 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-1230. Goldgar DE et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-2009. McConville CM et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996 Aug;59(2):320-30 Mitui M et al. Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat. 2009 Jan;30(1):12-21 Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-345. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-446. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.
Comment:
This missense variant replaces valine with glycine at codon 2424 in the FAT domain of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a significantly decreased ATM kinase activity (PMID: 11382771, 11830610, 18634022). This variant has been reported in over 50 individuals affected with breast cancer (PMID: 9463314, 11830610, 16958054, 21787400, 24733792, 25186627, 26681312, 27595995, 27798748, 28779002). Several large breast cancer case-control studies reported this variant to confer increased risk of the disease (PMID: 27595995, 33471991, 33509806), comparable to BRCA1 and BRCA2 pathogenic mutations (PMID: 11830610, 16958054, 26662178). This variant has been observed in multiple families affected with attenuated ataxia-telangiectasia in homozygous state or compound heterozygous state with pathogenic truncation variants (PMID: 8755918, 9463314, 18575927, 27528516, 30549301, 32748564). This variant has been identified in 12/282354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2424 of the ATM protein (p.Val2424Gly). This variant is present in population databases (rs28904921, gnomAD 0.01%). This missense change has been observed in individual(s) with gastric cancer, breast cancer, autosomal recessive ataxia-telangiectasia (PMID: 8755918, 9463314, 11830610, 16958054, 18575927, 19781682, 21787400, 24733792, 26506520). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3023). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 11382771, 11830610, 18634022, 19431188). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (AT; MIM#208900) and cancer susceptibility (MIM#114480). (I) 0106 - This gene is associated with autosomal recessive ataxia-telangiectasia. However, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastic, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMID: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (12 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated FAT domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals in a homozygous or compound heterozygous state with ataxia-telangiectasia, with a predominantly mild form of disease (ClinVar, PMID: 9463314, 30549301). This variant has also been reported to cause a significantly increased risk of breast cancer in heterozygous females (ClinVar, PMID: 27595995). Lifetime risk of breast cancer in women heterozygous for this variant is 52-69% (PMID: 16958054, 26662178). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on patient cells and transfected human cell lines show that this variant results in protein expression similar to wild-type, but significantly reduced kinase activity (PMID: 11382771, 18634022). This variant may act in a dominant negative manner (PMID: 11830610, 17001622). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The p.V2424G pathogenic mutation (also known as c.7271T>G), located in coding exon 48 of the ATM gene, results from a T to G substitution at nucleotide position 7271. The valine at codon 2424 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with ataxia-telangiectasia (AT) (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Marelli C et al. Hum. Mutat. 2016 Dec;37:1340-1353), colorectal cancer (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471) as well as individuals with personal history of breast cancer (Kurian AW et al. J. Clin. Oncol. 2014 Jul;32:2001-9; Tung N et al. Cancer. 2015 Jan;121:25-33; Southey MC et al. J. Med. Genet. 2016 12;53:800-811; Susswein LR et al. Genet. Med. 2016 08;18:823-32; Moran O et al. Breast Cancer Res. Treat. 2017 01;161:135-142; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This alteration impacts an evolutionarily conserved residue in the 3' FAT functional domain of the ATM protein and has been shown to act in a dominant-negative manner (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Waddell N et al. Genes Chromosomes Cancer. 2006 Dec;45:1169-81). In a large case-control study the p.V2424G pathogenic mutation was shown to be associated with a significantly increased risk for breast cancer (OR=11.0, 95% CI 1.42 to 85.7) (Southey MC et al. J. Med. Genet. 2016 12;53:800-811). Pedigree analyses of numerous p.V2424G-carrier families with multiple cases of breast cancer have produced lifetime cumulative breast cancer risk estimates ranging from 52% to 69% for this specific allele (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Chenevix-Trench G et al. J. Natl. Cancer Inst. 2002 Feb;94:205-15; Bernstein JL et al. Hum. Mutat. 2006 Nov;27:1122-8; Goldgar D et al. Breast Cancer Res. 2011 Jul;13:R73). Functional assays show that this mutation retains some residual kinase activity and has been seen in some patients with a milder AT phenotype (Thompson D et al. J. Natl. Cancer Inst. 2005 Jun;97:813-22; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Comment:
This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 18634022]. This variant has seen observed at the heterozygous state in at least 24 patients from two cohorts of breast cancer patients [PMID 19781682, 21787400]. Statistical analysis in one cohort estimated the risk factor for breast cancer to be 8.0 for carriers of this variant compared to 4.4 for families carriers of other pathogenic variants. This variant was observed in 3 Europeans (Non Finnish) at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/11-108199929-T-G). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Val2424Gly change to be deleterious. It is thus interpreted as a pathogenic variant.
Comment:
PP3, PS3_Moderate, PS4, PM3_Very strong, PP1
Comment:
The frequency of this variant in the general population, 0.000085 (11/128854 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals/families with breast cancer (PMIDs: 32427313 (2020), 27798748 (2017), 25186627 (2015), 24733792 (2014), 16958054 (2006), 16832357 (2006), 17001622 (2006), 14562025 (2003)) as well as individuals with other cancers such as gastric, prostate, or leukemia (PMIDs: 32338768 (2020), 26506520 (2015), 9892178 (1999), 9288106 (1997)). This variant was shown to be strongly associated with breast cancer risk among Caucasian women (PMIDs: 27595995 (2016), 21787400 (2011)), with estimated cumulative breast cancer risk to age 70 years (penetrance) 34-60% (PMIDs: 17001622 (2006), 16958054 (2006), 11830610 (2002)). In addition, this variant has been reported in individuals/families with ataxia-telangiectasia (PMIDs: 30549301 (2019), 18575927 (2008), 9463314 (1998), 8755918 (1996)). Furthermore, experimental studies have demonstrated that this variant results in reduced/null ATM kinase activity (PMID: 18634022 (2009), 11830610 (2002), 11382771 (2001)). Based on the available information, this variant is classified as pathogenic.
Comment:
PS3_Moderate,PS4,PM3_Strong,PP3
Comment:
Found in a male patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with bilateral breast cancer diagnosed at age 88 and 93.
Comment:
The ATM p.Val2424Gly variant was identified in 20 of 14588 proband chromosomes (frequency: 0.0013) from individuals or families with contralateral and bilateral breast cancers (Bernstein 2003, Bernstein 2010, Chenevix-Trench 2002, Goldgar 2011, Waddell 2006). The variant was also identified in dbSNP (ID: rs28904921) as “with pathogenic allele”, in the ClinVar database (as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 additional clinical laboratories, and as likely pathogenic by Counsyl), in the Cosmic database (2x as pathogenic), and in the LOVD 3.0 database (6x as pathogenic). The variant was not identified in the COGR or in the MutDB databases. The variant was also identified in control databases including the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles and in 14 of 276788 chromosomes at a frequency of 0.00005 in the Genome Aggregation Database (Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34412 chromosomes (freq: 0.00003), and European Non-Finnish in 13 of 126414 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vivo analyses of cell lines established from individuals heterozygous for the c.7271T>G variant suggest that this ATM variant acts in a dominant negative manner so that the wild-type enzyme is unable to function normally in the presence of the mutant protein. Results reveal that the mutant ATM protein from the c.7271T>G heterozygotes is stable but intrinsically defective as a kinase. It appears that, in cells with these mutant ATM alleles, p53 phosphorylation and stabilization are reduced, which presumably decreases the effectiveness of the cell cycle checkpoint (Chenevix-Trench 2002). In another study, the c.7271T>G variant was genotyped and modified segregation analysis was used to estimate the breast cancer penetrance. Women carrying the variant, ATM c.7271T>G demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2. Separate analyses of the 15 families carrying the ATM c.7271T>G variant found that this variant increased breast cancer risk by a factor of 8.0 compared with 4.4 for families with other ATM variants (Goldgar 2011). Another study confirmed that the p.Val2424Gly variant confers a moderate risk of breast cancer, with an estimated hazard ratio of 6.1. Furthermore, the study revealed that the V2424 allele was found across seven vertebrate sequences. To elucidate the molecular effects of the ATM 7271T>G variant, a study carried out expression profiling and demonstrated that the ATM 7271T>G variant acts largely as a dominant negative causing differences in expression profiles of many genes (Waddell 2006). The p.Val2424 residue is conserved across mammals and other 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 4 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 this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The ATM c.7271T>G variant is predicted to result in the amino acid substitution p.Val2424Gly. This variant has been reported in individuals with ataxia telangiectasia (Stankovic et al. 1998. PubMed ID: 9463314; McConville et al. 1996. PubMed ID: 8755918), multiple individuals with breast cancer (see for example - Bernstein et al. 2006. PubMed ID: 16958054; Goldgar et al. 2011. PubMed ID: 21787400), and one individual with gastric cancer (Huang et al. 2015. PubMed ID: 26506520). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3023/). This variant is interpreted as pathogenic.
Comment:
Variant interpretted as pathogenic and reported on 11/30/2017 by GTR ID Trillium Health Partners. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Ataxia-Telangiectasia. | Adam MP | - | 2023 | PMID: 20301790 |
| Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study. | Li N | NPJ breast cancer | 2021 | PMID: 34117267 |
| Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers. | Hall MJ | Cancer prevention research (Philadelphia, Pa.) | 2021 | PMID: 33509806 |
| 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 |
| Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. | Darst BF | Journal of the National Cancer Institute | 2021 | PMID: 32853339 |
| Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene). | Asadollahi R | Molecular genetics & genomic medicine | 2020 | PMID: 32748564 |
| Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. | Palmer JR | Journal of the National Cancer Institute | 2020 | PMID: 32427313 |
| Rare germline genetic variants and risk of aggressive prostate cancer. | Nguyen-Dumont T | International journal of cancer | 2020 | PMID: 32338768 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: [email protected] | American journal of human genetics | 2019 | PMID: 31447099 |
| Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. | Schon K | Annals of neurology | 2019 | PMID: 30549301 |
| Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. | Sun M | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29915382 |
| Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review. | Jerzak KJ | Current oncology (Toronto, Ont.) | 2018 | PMID: 29719442 |
| 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 |
| ATM mutations for surgeons. | Mansfield SA | Familial cancer | 2017 | PMID: 27988859 |
| Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
| Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel. | Moran O | Breast cancer research and treatment | 2017 | PMID: 27798748 |
| Ataxia telangiectasia: a review. | Rothblum-Oviatt C | Orphanet journal of rare diseases | 2016 | PMID: 27884168 |
| PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. | Southey MC | Journal of medical genetics | 2016 | PMID: 27595995 |
| Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias. | Marelli C | Human mutation | 2016 | PMID: 27528516 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. | van Os NJ | Clinical genetics | 2016 | PMID: 26662178 |
| Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
| Prevalence of deleterious ATM germline mutations in gastric cancer patients. | Huang DS | Oncotarget | 2015 | PMID: 26506520 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| 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 |
| Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. | Kurian AW | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2014 | PMID: 24733792 |
| ATM mutations in patients with hereditary pancreatic cancer. | Roberts NJ | Cancer discovery | 2012 | PMID: 22585167 |
| Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. | George Priya Doss C | PloS one | 2012 | PMID: 22529920 |
| Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. | Reiman A | British journal of cancer | 2011 | PMID: 21792198 |
| Rare variants in the ATM gene and risk of breast cancer. | Goldgar DE | Breast cancer research : BCR | 2011 | PMID: 21787400 |
| Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. | Tavtigian SV | American journal of human genetics | 2009 | PMID: 19781682 |
| Modeling ATM mutant proteins from missense changes confirms retained kinase activity. | Barone G | Human mutation | 2009 | PMID: 19431188 |
| Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. | Mitui M | Human mutation | 2009 | PMID: 18634022 |
| Attenuated presentation of ataxia-telangiectasia with familial cancer history. | Simonin C | Journal of neurology | 2008 | PMID: 18575927 |
| Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling. | Waddell N | Genes, chromosomes & cancer | 2006 | PMID: 17001622 |
| Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. | Bernstein JL | Human mutation | 2006 | PMID: 16958054 |
| ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. | Renwick A | Nature genetics | 2006 | PMID: 16832357 |
| Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease. | Takagi M | Blood | 2004 | PMID: 12969974 |
| ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer. | Bernstein JL | British journal of cancer | 2003 | PMID: 14562025 |
| Re: Dominant negative ATM mutations in breast cancer families. | Lei H | Journal of the National Cancer Institute | 2002 | PMID: 12072552 |
| Dominant negative ATM mutations in breast cancer families. | Chenevix-Trench G | Journal of the National Cancer Institute | 2002 | PMID: 11830610 |
| Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. | Scott SP | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11805335 |
| Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype. | Stewart GS | The Journal of biological chemistry | 2001 | PMID: 11382771 |
| ATM mutations in B-cell chronic lymphocytic leukemia. | Bullrich F | Cancer research | 1999 | PMID: 9892178 |
| ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. | Stankovic T | American journal of human genetics | 1998 | PMID: 9463314 |
| Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. | Vorechovský I | Nature genetics | 1997 | PMID: 9288106 |
| Mutations associated with variant phenotypes in ataxia-telangiectasia. | McConville CM | American journal of human genetics | 1996 | PMID: 8755918 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/36ae7580-8da9-4ce9-9040-32e7eee1bb34 | - | - | - | - |
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Text-mined citations for rs28904921 ...
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Record last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.