11-108227849-C-G
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP2_StrongBA1
This summary comes from the ClinGen Evidence Repository: The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA202190/MONDO:0016419/020
Frequency
Genomes: 𝑓 0.0072 ( 6 hom., cov: 33)
Exomes 𝑓: 0.011 ( 126 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
6
12
Clinical Significance
Conservation
PhyloP100: 2.00
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP2
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.146C>G | p.Ser49Cys | missense_variant | 3/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.00727 AC: 1105AN: 152090Hom.: 6 Cov.: 33
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GnomAD4 exome AF: 0.0114 AC: 16678AN: 1461052Hom.: 126 Cov.: 32 AF XY: 0.0111 AC XY: 8053AN XY: 726760
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GnomAD4 genome 0.00724 AC: 1102AN: 152206Hom.: 6 Cov.: 33 AF XY: 0.00640 AC XY: 476AN XY: 74416
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:33Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:10
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 27, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 17, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 07, 2021 | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2018 | Variant summary: ATM c.146C>G (p.Ser49Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 277324 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.013 in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold above the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). The allele frequency of this variant in a cohort of individuals who are cancer-free and older than 70 years is 0.025 (185/7325), which is even higher than the allele frequency in the general controls (gnomAD Non-Finnish European, 0.013). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.146C>G variant has been reported in the literature in individuals affected with Breast Cancer, though one study reported a lack of cosegregation of the variant with disease in two family members of a proband (Allinen_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. A case control study seeking to evaluate whether the variant increases the risk of breast cancer raised the possibility that the variant may be a breast cancer susceptibility allele (Stredrick_2006). However, a much larger cohort from Fletcher_2012 failed to prove the same. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 07, 2021 | - - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Ataxia-telangiectasia syndrome Benign:6
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 01, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 14, 2019 | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Nov 20, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
not provided Benign:6
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 28, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 28, 2015 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | ATM: BP4, BS1, BS2 - |
Hereditary cancer-predisposing syndrome Benign:6
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2014 | 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. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 14, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2017 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 08, 2020 | - - |
Familial cancer of breast Benign:3
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 17, 2024 | This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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]. - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
| Benign, reviewed by expert panel | curation | ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen | Mar 09, 2022 | The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. - |
Tip-toe gait Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Oct 06, 2020 | - - |
Malignant tumor of breast Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Ser49Cys variant was identified in 84 of 6116 proband chromosomes (frequency: 0.01) from individuals or families with ataxia telangiectasia and breast cancer and was present in 58 of 7048 control chromosomes (frequency: 0.008) from healthy individuals (Castellvi-Bei 1999, Petereit 2013, Schneider 2006, Stedrick 2006). The variant was identified in dbSNP (rs1800054) as “with uncertain significance, other allele”, ClinVar (classified as benign by Color, Ambry Genetics, Invitae and 6 other submitters and likely benign by True Health Diagnostics, University of Chicago and 5 other submitters) and LOVD 3.0 (observed 10x). The variant was identified in control databases in 2005 of 276,924 chromosomes (12 homozygous) at a frequency of 0.007 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 65 of 24,012 chromosomes (freq: 0.003), Other in 30 of 6462 chromosomes (freq: 0.005), Latino in 105 of 34,412 chromosomes (freq: 0.003), European in 1615 of 126,588 chromosomes (freq: 0.01), Ashkenazi Jewish in 6 of 10,148 chromosomes (freq: 0.0006), Finnish in 67 of 25,760 chromosomes (freq: 0.003) and South Asian in 117 of 30,674 chromosomes (freq: 0.004). The variant was not observed in the East Asian population. The variant was expressed in vitro and had reduced but detectable levels of ATM (Becker-Catania 2000). The p.Ser49 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 this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Breast cancer, susceptibility to Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T;T;.;T;T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T;T;T;.;.;.;.;.;T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;D;D;.;N;.;.;.;.;.
REVEL
Benign
Sift
Uncertain
D;D;D;D;.;D;.;.;.;.;.
Sift4G
Uncertain
D;D;D;D;D;D;.;.;.;D;D
Polyphen
0.98, 0.83
.;D;.;.;.;D;P;P;P;P;.
Vest4
0.42, 0.40, 0.50, 0.40
MVP
MPC
0.48
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at