rs148993589
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000051.4(ATM):c.4362A>C(p.Lys1454Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,818 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00041 ( 1 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 2.89
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 Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.09226492).
BP6
Variant 11-108289727-A-C is Benign according to our data. Variant chr11-108289727-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127386.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=9, Benign=2}. Variant chr11-108289727-A-C is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.4362A>C | p.Lys1454Asn | missense_variant | 29/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.4362A>C | p.Lys1454Asn | missense_variant | 29/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.000243 AC: 37AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000303 AC: 76AN: 251182Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135770
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GnomAD4 exome AF: 0.000413 AC: 603AN: 1461462Hom.: 1 Cov.: 31 AF XY: 0.000425 AC XY: 309AN XY: 727034
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GnomAD4 genome 0.000243 AC: 37AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74510
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:8Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 07, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 07, 2023 | The frequency of this variant in the general population, 0.00058 (75/129022 chromosomes in European (Non-Finnish) subpop subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 19781682 (2009), 17393301 (2008), 11505391 (2001)), endometrial cancer (PMID: 27443514 (2016)), colorectal cancer (PMID: 27978560 (2016)), pancreatic cancer (PMID: 33436325 (2021)), melanoma (PMID: 34262154 (2021)), or chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as an individual with perifoveal telangiectasia (PMID: 18502988 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 05, 2023 | BP4 - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Lys1454Asn variant was identified in 6 of 10774 proband chromosomes (frequency: 0.00056) from individuals or families with breast and colon cancer (Barbazetto_2008, Broeks_2008, Maillet_2002, Pearlman_2016, Tavtigian_2009, Teraoka_2001). The variant was also identified in dbSNP (ID: rs148993589) as “With Uncertain significance allele”, ClinVar (as benign by Ambry Genetics and as uncertain significance by GeneDx, Invitae, and Color Genomics), Clinvitae (as in ClinVar), and in Cosmic. The variant was not identified in the COGR, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 84 of 276958 chromosomes at a frequency of 0.000303 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.000042), Other in 1 of 6452 chromosomes (freq: 0.000155), European (Non-Finnish) in 76 of 126554 chromosomes (freq: 0.000601), Ashkenazi Jewish in 3 of 10138 chromosomes (freq: 0.000296), and European (Finnish) in 3 of 25770 chromosomes (freq: 0.000116); it was not observed in the Latino, East Asian, and South Asian populations. The p.Lys1454Asn residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant was identified in a laboratory in one individual with a co-occurring pathogenic BRCA2 variant p.Gln2943ArgfsX33 in a family with HBOC, increasing the likelihood that the p.Lys1454Asn variant does not have clinical significance. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | ATM: PM2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, endometrial, or colon cancer (Maillet 2002, Broeks 2008, Tavtigian 2009, Lu 2015, Tung 2015, Ring 2016, Decker 2017, Pearlman 2017, Hampel 2018, Hauke 2018); Observed in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008); This variant is associated with the following publications: (PMID: 19781682, 12362033, 17393301, 22529920, 26689913, 12697903, 11505391, 27978560, 27443514, 25925381, 28779002, 25186627, 29522266, 29596542, 30197789, 10425038, 27150160, 25759019, 18502988, 33471991) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 03, 2017 | The p.Lys1454Asn variant has been reported in individuals with breast cancer (Broeks 2008 Teraoka 2001, Tavtigian 2009), endometrial cancer (Ring 2016), and idiopathic perifoveal telangiectasia (Barbazetto 2008) but has not been reported in association with ataxia telangiectasia. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03 percent (identified on 84 out of 276,958 chromosomes) and has been reported to ClinVar (Variation ID: 127386). The lysine at position 1454 is moderately conserved (Alamut v.2.9.0) and computational analyses of the effects of the p.Lys1454Asn variant on protein structure and function predict a neutral effect (SIFT: tolerated, Align GVGC: C0 (benign), PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Lys1454Asn variant with certainty. - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 12, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2015 | 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. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 21, 2020 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The amino acid Lys at position 1454 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The missense variant c.4362A>C (p.Lys1454Asn) in ATM gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Lys1454Asn variant is reported with the allele frequency of 0.02937% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Lys1454Asn in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Familial cancer of breast Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Nov 25, 2019 | This variant has been reported in the literature in individuals with breast cancer and in an individual with endometrial cancer (Teraoka 2001, Broeks 2008, Tavtigian 2009, Lu 2015, Ring 2016), as well as in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008). This variant has an overall allele frequency of 0.0003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 17, 2024 | 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]. - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant summary: ATM c.4362A>C (p.Lys1454Asn) results in a non-conservative amino acid change in 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 0.0003 in 259596 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0003 vs 0.004), allowing no conclusion about variant significance. c.4362A>C has been reported in the literature in individuals undergoing multigene panel testing for a variety of hereditary cancers without strong evidence for causality (e.g. Broeks_2008, Tavtigian_2009, Tung_2015, Dalmasso_2021, Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. 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: 17393301, 18502988, 19781682, 22529920, 20305132, 17623063, 25186627, 10425038, 28652578, 30447919, 30584090, 31173964, 33436325, 34262154). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=5) and VUS (n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over 5 years of review performed at our laboratory and in the literature as evidence outlined above, the variant was re-classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
ATM-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 18, 2024 | The ATM c.4362A>C variant is predicted to result in the amino acid substitution p.Lys1454Asn. This variant has been observed among multiple patients with sporadic and familial breast cancer, some of whom had additional variants in the BRCA1 or BRCA2 genes; however, this variant was also detected in controls in at least one study (Teraoka et al. 2001. PubMed ID: 11505391; Maillet et al. 2002. PubMed ID: 12362033; Broeks et al. 2008. PubMed ID: 17393301; Tavtigian et al. 2009, Table S2, PubMed ID: 19781682; Table S12, Lu et al. 2015. PubMed ID: 26689913). It has also been reported in individuals with early-onset colorectal cancer (Pearlman et al. 2017. eTable 2, PubMed ID: 27978560), endometrial cancer (Ring et al. 2016, Table S2, PubMed ID: 27443514) and bilateral idiopathic perifoveal telangiectasia (Barbazetto et al. 2008. PubMed ID: 18502988). In addition, Fang et al. has mentioned it as a somatic variant in mantle cell lymphoma (Fang et al. 2003. PubMed ID: 12697903). This variant has been reported at a frequency of ~0.06% in individuals of non-Finnish European origin in the gnomAD database. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127386/). While this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
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
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Benign
T;T;.
Sift4G
Uncertain
T;T;D
Polyphen
B;B;.
Vest4
MutPred
Loss of ubiquitination at K1454 (P = 0.0183);Loss of ubiquitination at K1454 (P = 0.0183);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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