This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.7390T>C (p.Cys2464Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(22)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(9); Benign(5); Likely benign(5)
Uncertain significance(9); Benign(5); Likely benign(5)
22
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.7390T>C (p.Cys2464Arg)
Variation ID: 127443 Accession: VCV000127443.77
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108330296 (GRCh38) [ NCBI UCSC ] 11: 108201023 (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 Dec 27, 2015 Oct 20, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.7390T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Cys2464Arg missense NM_001330368.2:c.641-21225A>G intron variant NM_001351110.2:c.*38+4924A>G intron variant NM_001351834.2:c.7390T>C NP_001338763.1:p.Cys2464Arg missense NC_000011.10:g.108330296T>C NC_000011.9:g.108201023T>C NG_009830.1:g.112465T>C NG_054724.1:g.144537A>G LRG_135:g.112465T>C LRG_135t1:c.7390T>C LRG_135p1:p.Cys2464Arg Q13315:p.Cys2464Arg - Protein change
- C2464R
- Other names
-
p.C2464R:TGT>CGT
- Canonical SPDI
- NC_000011.10:108330295:T:C
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00032
The Genome Aggregation Database (gnomAD) 0.00038
The Genome Aggregation Database (gnomAD), exomes 0.00043
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
Exome Aggregation Consortium (ExAC) 0.00057
- 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 |
10839 | 17439 | |
| C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6582 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jun 9, 2021 | RCV000115249.22 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Feb 1, 2024 | RCV000119204.38 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jul 31, 2024 | RCV000202803.22 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jun 1, 2024 | RCV000589438.41 | |
| Likely benign (1) |
no assertion criteria provided
|
- | RCV001356727.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 9, 2023 | RCV001798325.12 | |
|
ATM-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Mar 19, 2024 | RCV004549571.3 |
| Likely benign (1) |
criteria provided, single submitter
|
Jun 13, 2024 | RCV004589576.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely benign
(Jun 09, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537670.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Benign
(Nov 12, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186389.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain significance
(Jul 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000257606.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138562.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely benign
(Oct 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473046.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
|
|
Likely benign
(Sep 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149158.11
First in ClinVar: May 17, 2014 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 30093976, 30303537, 30197789, 17623063, 20305132, 22250480, 21933854, 23555315, 25479140, 28135145, 28779002, 25587027, 15279808, 22420423, 12810666, 27978560, … (more)
This variant is associated with the following publications: (PMID: 30093976, 30303537, 30197789, 17623063, 20305132, 22250480, 21933854, 23555315, 25479140, 28135145, 28779002, 25587027, 15279808, 22420423, 12810666, 27978560, 27878467, 26787654, 17344846, 11805335, 11606401, 11839094, 16652348, 12673804, 23091097, 22529920, 19781682) (less)
|
|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010786.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Benign
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222143.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
|
|
|
Uncertain significance
(Mar 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003827470.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042887.3
First in ClinVar: Jan 03, 2022 Last updated: Feb 04, 2024 |
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000153946.14
First in ClinVar: Jun 03, 2014 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760693.5
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
|
|
|
Benign
(Nov 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000910578.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Benign
(Feb 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694351.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three … (more)
Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00042 vs 0.001). However, this variant has been reported in 16/9884 (0.0016) women older than age 70 and cancer free. This frequency is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs 0.001), suggesting this variant does not associate with cancer. c.7390T>C has been reported in the literature in individuals affected with Breast Cancer. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (CHEK2 c.1100delC, p.Thr367fsX15; TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (1x Benign, 2 x Likely benign, 4x VUS). Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001261060.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Jun 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Accession: SCV001911484.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Comment:
The c.7390T>C (p.Cys2464Arg) variant has an allele frequency of 0.00043 (0.04%, 114/268,152 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00092 … (more)
The c.7390T>C (p.Cys2464Arg) variant has an allele frequency of 0.00043 (0.04%, 114/268,152 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00092 (0.09%, 109/118,016 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026). (less)
Clinical Features:
Ocular melanoma (present)
Indication for testing: Malignant Melanoma Susceptibility
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
|
|
|
Uncertain significance
(Nov 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070990.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
|
Likely benign
(Jun 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV005083932.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
|
|
|
Uncertain significance
(Jun 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780404.29
First in ClinVar: Mar 17, 2018 Last updated: Oct 20, 2024 |
Comment:
ATM: PM2:Supporting, BS3:Supporting
Number of individuals with the variant: 5
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551971.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Cys2464Arg variant was identified in 25 of 16960 proband chromosomes (frequency: 0.002) from individuals or families with B chronic lymphocytic leukemia, breast cancer … (more)
The ATM p.Cys2464Arg variant was identified in 25 of 16960 proband chromosomes (frequency: 0.002) from individuals or families with B chronic lymphocytic leukemia, breast cancer or pancreatic cancer and was present in 18 of 5488 control chromosomes (frequency: 0.003) from healthy individuals (Athanasakis 2014, Bernstein 2010, Decker 2017, Dork 2001, Grant 2015, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs55801750) as "With other allele", ClinVar (classified as Benign by Ambry Genetics; as likely benign by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by four submitters), and in LOVD 3.0 (2x as unclassified variant). The variant was identified in control databases in 118 of 277014 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 114 of 126536 chromosomes (freq: 0.0009), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys2464 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
Number of individuals with the variant: 1
|
|
|
Likely benign
(Feb 14, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002080599.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Uncertain significance
(Mar 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ATM-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004113598.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The ATM c.7390T>C variant is predicted to result in the amino acid substitution p.Cys2464Arg. This variant has been identified in individuals with breast cancer (Table … (more)
The ATM c.7390T>C variant is predicted to result in the amino acid substitution p.Cys2464Arg. This variant has been identified in individuals with breast cancer (Table 1, Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Decker et al. 2017. PubMed ID: 28779002). This variant was also identified in an individual with colorectal cancer with deficient DNA mismatch repair activity, and who also had constitutional MLH1 promoter methylation (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). Functional in vitro and in vivo analysis showed that this variant had normal induction of ATM kinase activity, and potentially does not interfere with ATM function (Scott et al. 2002. PubMed ID: 11805335). This variant is reported in 0.091% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127443/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is associated with the following publications: (PMID: 30093976, 30303537, 30197789, 17623063, 20305132, 22250480, 21933854, 23555315, 25479140, 28135145, 28779002, 25587027, 15279808, 22420423, 12810666, 27978560, 27878467, 26787654, 17344846, 11805335, 11606401, 11839094, 16652348, 12673804, 23091097, 22529920, 19781682)
Comment:
Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00042 vs 0.001). However, this variant has been reported in 16/9884 (0.0016) women older than age 70 and cancer free. This frequency is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs 0.001), suggesting this variant does not associate with cancer. c.7390T>C has been reported in the literature in individuals affected with Breast Cancer. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (CHEK2 c.1100delC, p.Thr367fsX15; TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (1x Benign, 2 x Likely benign, 4x VUS). Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
The c.7390T>C (p.Cys2464Arg) variant has an allele frequency of 0.00043 (0.04%, 114/268,152 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00092 (0.09%, 109/118,016 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Comment:
ATM: PM2:Supporting, BS3:Supporting
Comment:
The ATM p.Cys2464Arg variant was identified in 25 of 16960 proband chromosomes (frequency: 0.002) from individuals or families with B chronic lymphocytic leukemia, breast cancer or pancreatic cancer and was present in 18 of 5488 control chromosomes (frequency: 0.003) from healthy individuals (Athanasakis 2014, Bernstein 2010, Decker 2017, Dork 2001, Grant 2015, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs55801750) as "With other allele", ClinVar (classified as Benign by Ambry Genetics; as likely benign by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by four submitters), and in LOVD 3.0 (2x as unclassified variant). The variant was identified in control databases in 118 of 277014 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 114 of 126536 chromosomes (freq: 0.0009), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys2464 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Comment:
The ATM c.7390T>C variant is predicted to result in the amino acid substitution p.Cys2464Arg. This variant has been identified in individuals with breast cancer (Table 1, Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Decker et al. 2017. PubMed ID: 28779002). This variant was also identified in an individual with colorectal cancer with deficient DNA mismatch repair activity, and who also had constitutional MLH1 promoter methylation (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). Functional in vitro and in vivo analysis showed that this variant had normal induction of ATM kinase activity, and potentially does not interfere with ATM function (Scott et al. 2002. PubMed ID: 11805335). This variant is reported in 0.091% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127443/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant is associated with the following publications: (PMID: 30093976, 30303537, 30197789, 17623063, 20305132, 22250480, 21933854, 23555315, 25479140, 28135145, 28779002, 25587027, 15279808, 22420423, 12810666, 27978560, 27878467, 26787654, 17344846, 11805335, 11606401, 11839094, 16652348, 12673804, 23091097, 22529920, 19781682)
Comment:
Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00042 vs 0.001). However, this variant has been reported in 16/9884 (0.0016) women older than age 70 and cancer free. This frequency is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs 0.001), suggesting this variant does not associate with cancer. c.7390T>C has been reported in the literature in individuals affected with Breast Cancer. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (CHEK2 c.1100delC, p.Thr367fsX15; TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (1x Benign, 2 x Likely benign, 4x VUS). Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
The c.7390T>C (p.Cys2464Arg) variant has an allele frequency of 0.00043 (0.04%, 114/268,152 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00092 (0.09%, 109/118,016 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Comment:
ATM: PM2:Supporting, BS3:Supporting
Comment:
The ATM p.Cys2464Arg variant was identified in 25 of 16960 proband chromosomes (frequency: 0.002) from individuals or families with B chronic lymphocytic leukemia, breast cancer or pancreatic cancer and was present in 18 of 5488 control chromosomes (frequency: 0.003) from healthy individuals (Athanasakis 2014, Bernstein 2010, Decker 2017, Dork 2001, Grant 2015, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs55801750) as "With other allele", ClinVar (classified as Benign by Ambry Genetics; as likely benign by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by four submitters), and in LOVD 3.0 (2x as unclassified variant). The variant was identified in control databases in 118 of 277014 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 114 of 126536 chromosomes (freq: 0.0009), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys2464 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Comment:
The ATM c.7390T>C variant is predicted to result in the amino acid substitution p.Cys2464Arg. This variant has been identified in individuals with breast cancer (Table 1, Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Decker et al. 2017. PubMed ID: 28779002). This variant was also identified in an individual with colorectal cancer with deficient DNA mismatch repair activity, and who also had constitutional MLH1 promoter methylation (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). Functional in vitro and in vivo analysis showed that this variant had normal induction of ATM kinase activity, and potentially does not interfere with ATM function (Scott et al. 2002. PubMed ID: 11805335). This variant is reported in 0.091% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127443/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome. | Veloza L | Haematologica | 2023 | PMID: 35708139 |
| 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 |
| The association between ATM variants and risk of breast cancer: a systematic review and meta-analysis. | Moslemi M | BMC cancer | 2021 | PMID: 33402103 |
| A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
| Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
| Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
| Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
| Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
| Outcomes of retesting BRCA negative patients using multigene panels. | Yadav S | Familial cancer | 2017 | PMID: 27878467 |
| Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
| Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients. | Wong SQ | British journal of cancer | 2015 | PMID: 25742471 |
| Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. | Grant RC | Gastroenterology | 2015 | PMID: 25479140 |
| The p53 transcriptional pathway is preserved in ATMmutated and NOTCH1mutated chronic lymphocytic leukemias. | Athanasakis E | Oncotarget | 2014 | PMID: 25587027 |
| Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
| Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
| Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. | Skowronska A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 23091097 |
| Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. | George Priya Doss C | PloS one | 2012 | PMID: 22529920 |
| Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer. | Knappskog S | Breast cancer research : BCR | 2012 | PMID: 22420423 |
| ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. | Skowronska A | Haematologica | 2012 | PMID: 21933854 |
| Analysis of D1853N ATM polymorphism in radiosensitive patients with cervical carcinoma. | Beránek M | Acta medica (Hradec Kralove) | 2011 | PMID: 22250480 |
| Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. | Bernstein JL | Journal of the National Cancer Institute | 2010 | PMID: 20305132 |
| Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. | Tavtigian SV | American journal of human genetics | 2009 | PMID: 19781682 |
| Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. | Edvardsen H | Radiation oncology (London, England) | 2007 | PMID: 17623063 |
| Patterns of somatic mutation in human cancer genomes. | Greenman C | Nature | 2007 | PMID: 17344846 |
| The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer. | Stredrick DL | Human mutation | 2006 | PMID: 16652348 |
| Functional consequences of sequence alterations in the ATM gene. | Lavin MF | DNA repair | 2004 | PMID: 15279808 |
| Contributions of ATM mutations to familial breast and ovarian cancer. | Thorstenson YR | Cancer research | 2003 | PMID: 12810666 |
| ATM gene alterations in childhood acute lymphoblastic leukemias. | Gumy Pause F | Human mutation | 2003 | PMID: 12673804 |
| 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 |
| Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. | Dörk T | Cancer research | 2001 | PMID: 11606401 |
| [Sulfatemia and clearance of anorganic sulfate in a control group]. | Popadić M | Medicinski arhiv | 1975 | PMID: 1160401 |
| click to load more click to collapse | ||||
Text-mined citations for rs55801750 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.