The best available variant frequency is uninformative because it is below the disease allele frequency. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. In the literature this variant was detected in a patient with breast cancer, another with stomach adenocarcinoma and another patient with chronic lymphocytic leukemia. However it was also seen in healthy controls. Based on the available information, we are unable to determine the clinical significance of this variant.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.8558C>T (p.Thr2853Met)
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.
(16)
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(11); Likely benign(1)
Uncertain significance(11); Likely benign(1)
16
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.8558C>T (p.Thr2853Met)
Variation ID: 142249 Accession: VCV000142249.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108345882 (GRCh38) [ NCBI UCSC ] 11: 108216609 (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 Feb 19, 2018 Oct 20, 2024 Aug 22, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.8558C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Thr2853Met missense NM_001330368.2:c.641-36811G>A intron variant NM_001351110.2:c.695-10590G>A intron variant NM_001351834.2:c.8558C>T NP_001338763.1:p.Thr2853Met missense NC_000011.10:g.108345882C>T NC_000011.9:g.108216609C>T NG_009830.1:g.128051C>T NG_054724.1:g.128951G>A LRG_135:g.128051C>T LRG_135t1:c.8558C>T LRG_135p1:p.Thr2853Met - Protein change
- T2853M
- Other names
-
p.T2853M:ACG>ATG
- Canonical SPDI
- NC_000011.10:108345881:C:T
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- 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 |
10850 | 17460 | |
| C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6592 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 24, 2023 | RCV000131262.25 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Nov 4, 2022 | RCV000203831.21 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2024 | RCV000589725.20 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356460.9 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Nov 14, 2023 | RCV002265616.14 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 19, 2021 | RCV002483265.8 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jun 20, 2024 | RCV003474776.3 | |
|
ATM-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Jul 23, 2024 | RCV004739452.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001475575.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
|
|
Uncertain significance
(Nov 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222268.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Analysis of this variant using bioinformatics tools for the prediction … (more)
The best available variant frequency is uninformative because it is below the disease allele frequency. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. In the literature this variant was detected in a patient with breast cancer, another with stomach adenocarcinoma and another patient with chronic lymphocytic leukemia. However it was also seen in healthy controls. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Mar 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204324.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(Aug 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209658.18
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26837699, 25503501, 26689913, 28779002, 28188106, 27304073, 25042771, 28652578, 30613976, 33436325, 34371384, 35039564, 32522261, 35365198, 30253992, 23532176, 36568162, 33471991, 36446039, 35171259, 37262986) (less)
|
|
|
Uncertain significance
(Mar 18, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529901.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ATM c.8558C>T (p.T2853M) variant has been reported in heterozygosity in individuals with breast cancer, chronic lymphoblastic leukemia, pancreatic cancer, and prostate cancer (PMID: 25503501, … (more)
The ATM c.8558C>T (p.T2853M) variant has been reported in heterozygosity in individuals with breast cancer, chronic lymphoblastic leukemia, pancreatic cancer, and prostate cancer (PMID: 25503501, 33471991, 26837699, 33436325, 34371384, 35039564, 28779002) but was also observed in control healthy populations (PMID: 33471991, 28652578). It was observed in 15/282472 chromosomes across all populations in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 142249). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Nov 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260783.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2853 of the ATM protein (p.Thr2853Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2853 of the ATM protein (p.Thr2853Met). This variant is present in population databases (rs141534716, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, gastric cancer, pancreatic cancer, and/or prostate cancer (PMID: 26689913, 26837699, 30613976, 33436325, 34371384). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in ATM in an individual who was not affected with recessive ATM-related conditions (Invitae). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 142249). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Oct 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186227.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T2853M variant (also known as c.8558C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide … (more)
The p.T2853M variant (also known as c.8558C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8558. The threonine at codon 2853 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 13087 breast cancer cases from the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Nov 14, 2023)
|
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: SCV000694380.5
First in ClinVar: Mar 17, 2018 Last updated: Jun 09, 2024 |
Comment:
Variant summary: ATM c.8558C>T (p.Thr2853Met) results in a non-conservative amino acid change located in the phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. … (more)
Variant summary: ATM c.8558C>T (p.Thr2853Met) results in a non-conservative amino acid change located in the phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.8558C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (e.g. Rizzolo_2019, Dorling_2021, Eygelaar_2022, van der Merwe_2022), early-onset prostate cancer (Trendowski_2022), and other types of cancer (e.g. Nadeu_2016, Yin_2022). However, it has also been reported in unaffected control individuals (e.g. Dorling_2021, Renault_2022). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 35039564, 25042771, 26837699, 35365198, 30613976, 35171259, 36568162, 36446039, 37262986). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Likely benign
(Jun 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV005084015.1
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
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005329794.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Oct 19, 2021)
|
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: SCV002784440.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Apr 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292153.6
First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 2853 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces threonine with methionine at codon 2853 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 33471991, 35039564), pancreatic cancer (PMID: 34371384), or chronic lymphocytic leukemia (PMID: 26837699), as well as in unaffected controls (PMID: 33471991, 35365198). This variant has been identified in 15/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jul 23, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ATM-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005354903.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ATM c.8558C>T variant is predicted to result in the amino acid substitution p.Thr2853Met. This variant has been reported in individuals with a history of … (more)
The ATM c.8558C>T variant is predicted to result in the amino acid substitution p.Thr2853Met. This variant has been reported in individuals with a history of breast cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Dorling et al. 2021. PubMed ID: 33471991; Table 2, Eygelaar et al. 2022. PubMed ID: 35039564), pancreatic cancer (Bono et al. 2021. PubMed ID: 34371384), or chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699); but has also been reported in control individuals (Dorling et al. 2021. PubMed ID: 33471991). Of note, a different missense variant at this same position (p.Thr2853Arg) has been reported in a patient with breast cancer (Supplementary Table 1, Maxwell et al. 2015. PubMed ID: 25503501). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is listed in ClinVar by multiple laboratories as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142249/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001452574.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Uncertain significance
(-)
|
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: SCV001551637.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Thr2853Met variant was identified in 1 of 796 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Nadeu 2015). The … (more)
The ATM p.Thr2853Met variant was identified in 1 of 796 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Nadeu 2015). The variant was also identified in dbSNP (ID: rs141534716) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 17 of 276798 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001), Latino in 1 of 34376 chromosomes (freq: 0.00003), European in 9 of 126386 chromosomes (freq: 0.00007), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 1 of 25776 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the Other or Ashkenazi Jewish populations. The p.Thr2853 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Feb 06, 2024)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV004242559 appears to be redundant with SCV005093943.
(less)
Notes: SCV004242559 appears to
(...more)
Source: NCBI
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242559.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26837699, 25503501, 26689913, 28779002, 28188106, 27304073, 25042771, 28652578, 30613976, 33436325, 34371384, 35039564, 32522261, 35365198, 30253992, 23532176, 36568162, 33471991, 36446039, 35171259, 37262986)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2853 of the ATM protein (p.Thr2853Met). This variant is present in population databases (rs141534716, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, gastric cancer, pancreatic cancer, and/or prostate cancer (PMID: 26689913, 26837699, 30613976, 33436325, 34371384). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in ATM in an individual who was not affected with recessive ATM-related conditions (Invitae). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 142249). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.T2853M variant (also known as c.8558C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8558. The threonine at codon 2853 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 13087 breast cancer cases from the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: ATM c.8558C>T (p.Thr2853Met) results in a non-conservative amino acid change located in the phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.8558C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (e.g. Rizzolo_2019, Dorling_2021, Eygelaar_2022, van der Merwe_2022), early-onset prostate cancer (Trendowski_2022), and other types of cancer (e.g. Nadeu_2016, Yin_2022). However, it has also been reported in unaffected control individuals (e.g. Dorling_2021, Renault_2022). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 35039564, 25042771, 26837699, 35365198, 30613976, 35171259, 36568162, 36446039, 37262986). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
This missense variant replaces threonine with methionine at codon 2853 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 33471991, 35039564), pancreatic cancer (PMID: 34371384), or chronic lymphocytic leukemia (PMID: 26837699), as well as in unaffected controls (PMID: 33471991, 35365198). This variant has been identified in 15/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The ATM c.8558C>T variant is predicted to result in the amino acid substitution p.Thr2853Met. This variant has been reported in individuals with a history of breast cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Dorling et al. 2021. PubMed ID: 33471991; Table 2, Eygelaar et al. 2022. PubMed ID: 35039564), pancreatic cancer (Bono et al. 2021. PubMed ID: 34371384), or chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699); but has also been reported in control individuals (Dorling et al. 2021. PubMed ID: 33471991). Of note, a different missense variant at this same position (p.Thr2853Arg) has been reported in a patient with breast cancer (Supplementary Table 1, Maxwell et al. 2015. PubMed ID: 25503501). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is listed in ClinVar by multiple laboratories as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142249/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The ATM p.Thr2853Met variant was identified in 1 of 796 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Nadeu 2015). The variant was also identified in dbSNP (ID: rs141534716) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 17 of 276798 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001), Latino in 1 of 34376 chromosomes (freq: 0.00003), European in 9 of 126386 chromosomes (freq: 0.00007), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 1 of 25776 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the Other or Ashkenazi Jewish populations. The p.Thr2853 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
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 best available variant frequency is uninformative because it is below the disease allele frequency. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. In the literature this variant was detected in a patient with breast cancer, another with stomach adenocarcinoma and another patient with chronic lymphocytic leukemia. However it was also seen in healthy controls. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26837699, 25503501, 26689913, 28779002, 28188106, 27304073, 25042771, 28652578, 30613976, 33436325, 34371384, 35039564, 32522261, 35365198, 30253992, 23532176, 36568162, 33471991, 36446039, 35171259, 37262986)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2853 of the ATM protein (p.Thr2853Met). This variant is present in population databases (rs141534716, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, gastric cancer, pancreatic cancer, and/or prostate cancer (PMID: 26689913, 26837699, 30613976, 33436325, 34371384). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in ATM in an individual who was not affected with recessive ATM-related conditions (Invitae). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 142249). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.T2853M variant (also known as c.8558C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8558. The threonine at codon 2853 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 13087 breast cancer cases from the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: ATM c.8558C>T (p.Thr2853Met) results in a non-conservative amino acid change located in the phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.8558C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (e.g. Rizzolo_2019, Dorling_2021, Eygelaar_2022, van der Merwe_2022), early-onset prostate cancer (Trendowski_2022), and other types of cancer (e.g. Nadeu_2016, Yin_2022). However, it has also been reported in unaffected control individuals (e.g. Dorling_2021, Renault_2022). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 35039564, 25042771, 26837699, 35365198, 30613976, 35171259, 36568162, 36446039, 37262986). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
This missense variant replaces threonine with methionine at codon 2853 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 33471991, 35039564), pancreatic cancer (PMID: 34371384), or chronic lymphocytic leukemia (PMID: 26837699), as well as in unaffected controls (PMID: 33471991, 35365198). This variant has been identified in 15/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The ATM c.8558C>T variant is predicted to result in the amino acid substitution p.Thr2853Met. This variant has been reported in individuals with a history of breast cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Dorling et al. 2021. PubMed ID: 33471991; Table 2, Eygelaar et al. 2022. PubMed ID: 35039564), pancreatic cancer (Bono et al. 2021. PubMed ID: 34371384), or chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699); but has also been reported in control individuals (Dorling et al. 2021. PubMed ID: 33471991). Of note, a different missense variant at this same position (p.Thr2853Arg) has been reported in a patient with breast cancer (Supplementary Table 1, Maxwell et al. 2015. PubMed ID: 25503501). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is listed in ClinVar by multiple laboratories as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142249/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The ATM p.Thr2853Met variant was identified in 1 of 796 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Nadeu 2015). The variant was also identified in dbSNP (ID: rs141534716) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 17 of 276798 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001), Latino in 1 of 34376 chromosomes (freq: 0.00003), European in 9 of 126386 chromosomes (freq: 0.00007), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 1 of 25776 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the Other or Ashkenazi Jewish populations. The p.Thr2853 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study. | Bucalo A | European journal of cancer (Oxford, England : 1990) | 2023 | PMID: 37262986 |
| Implementation of multigene panel testing for breast and ovarian cancer in South Africa: A step towards excellence in oncology for the public sector. | van der Merwe NC | Frontiers in oncology | 2022 | PMID: 36568162 |
| Germline Variants in DNA Damage Repair Genes and HOXB13 Among Black Patients With Early-Onset Prostate Cancer. | Trendowski MR | JCO precision oncology | 2022 | PMID: 36446039 |
| Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM. | Renault AL | Breast cancer research : BCR | 2022 | PMID: 35365198 |
| Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China. | Yin L | JAMA network open | 2022 | PMID: 35171259 |
| Germline sequence variants contributing to cancer susceptibility in South African breast cancer patients of African ancestry. | Eygelaar D | Scientific reports | 2022 | PMID: 35039564 |
| Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge. | Bono M | ESMO open | 2021 | PMID: 34371384 |
| 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 |
| A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection. | Velázquez C | Journal of translational medicine | 2020 | PMID: 32522261 |
| Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. | Rizzolo P | International journal of cancer | 2019 | PMID: 30613976 |
| Extensive Leptomeningeal Intracranial and Spinal Metastases in a Patient with a Supratentorial Glioblastoma Multiforme, IDH-Wildtype. | Schwartz C | World neurosurgery | 2018 | PMID: 30253992 |
| 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 |
| Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
| Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. | Nadeu F | Blood | 2016 | PMID: 26837699 |
| Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
| Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
| 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 |
| The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. | Kim TM | The Journal of pathology | 2014 | PMID: 25042771 |
| click to load more click to collapse | ||||
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Uncertain significance
criteria provided, single submitter
|
Jul 31, 2024 | RCV004668797.1 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005093943.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. In the literature this variant was detected in a patient with breast cancer, another with stomach adenocarcinoma and another patient with chronic lymphocytic leukemia. However it was also seen in healthy controls. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26837699, 25503501, 26689913, 28779002, 28188106, 27304073, 25042771, 28652578, 30613976, 33436325, 34371384, 35039564, 32522261, 35365198, 30253992, 23532176, 36568162, 33471991, 36446039, 35171259, 37262986)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2853 of the ATM protein (p.Thr2853Met). This variant is present in population databases (rs141534716, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, gastric cancer, pancreatic cancer, and/or prostate cancer (PMID: 26689913, 26837699, 30613976, 33436325, 34371384). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in ATM in an individual who was not affected with recessive ATM-related conditions (Invitae). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 142249). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.T2853M variant (also known as c.8558C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8558. The threonine at codon 2853 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 13087 breast cancer cases from the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: ATM c.8558C>T (p.Thr2853Met) results in a non-conservative amino acid change located in the phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.8558C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (e.g. Rizzolo_2019, Dorling_2021, Eygelaar_2022, van der Merwe_2022), early-onset prostate cancer (Trendowski_2022), and other types of cancer (e.g. Nadeu_2016, Yin_2022). However, it has also been reported in unaffected control individuals (e.g. Dorling_2021, Renault_2022). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 35039564, 25042771, 26837699, 35365198, 30613976, 35171259, 36568162, 36446039, 37262986). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
This missense variant replaces threonine with methionine at codon 2853 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 33471991, 35039564), pancreatic cancer (PMID: 34371384), or chronic lymphocytic leukemia (PMID: 26837699), as well as in unaffected controls (PMID: 33471991, 35365198). This variant has been identified in 15/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The ATM c.8558C>T variant is predicted to result in the amino acid substitution p.Thr2853Met. This variant has been reported in individuals with a history of breast cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Dorling et al. 2021. PubMed ID: 33471991; Table 2, Eygelaar et al. 2022. PubMed ID: 35039564), pancreatic cancer (Bono et al. 2021. PubMed ID: 34371384), or chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699); but has also been reported in control individuals (Dorling et al. 2021. PubMed ID: 33471991). Of note, a different missense variant at this same position (p.Thr2853Arg) has been reported in a patient with breast cancer (Supplementary Table 1, Maxwell et al. 2015. PubMed ID: 25503501). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is listed in ClinVar by multiple laboratories as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142249/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The ATM p.Thr2853Met variant was identified in 1 of 796 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Nadeu 2015). The variant was also identified in dbSNP (ID: rs141534716) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 17 of 276798 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001), Latino in 1 of 34376 chromosomes (freq: 0.00003), European in 9 of 126386 chromosomes (freq: 0.00007), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 1 of 25776 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the Other or Ashkenazi Jewish populations. The p.Thr2853 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs141534716 ...
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 25, 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.