11-108247060-C-T
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.998C>T(p.Ser333Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,876 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S333S) has been classified as Benign.
Frequency
Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 4 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 3.49
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 -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0085556805).
BP6
Variant 11-108247060-C-T is Benign according to our data. Variant chr11-108247060-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127471.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=15, Uncertain_significance=1, not_provided=1}. Variant chr11-108247060-C-T is described in Lovd as [Likely_benign]. Variant chr11-108247060-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00135 (206/152300) while in subpopulation AMR AF= 0.00405 (62/15300). AF 95% confidence interval is 0.00324. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.998C>T | p.Ser333Phe | missense_variant | 8/63 | ENST00000675843.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.998C>T | p.Ser333Phe | missense_variant | 8/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes 0.00135 AC: 206AN: 152182Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00156 AC: 392AN: 251168Hom.: 1 AF XY: 0.00141 AC XY: 191AN XY: 135758
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GnomAD4 exome AF: 0.00144 AC: 2099AN: 1461576Hom.: 4 Cov.: 31 AF XY: 0.00138 AC XY: 1007AN XY: 727076
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GnomAD4 genome 0.00135 AC: 206AN: 152300Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:27Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:10
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | ATM: BP1, BP4, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 28, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 17, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2016 | Variant summary: ATM c.998C>T affects a conserved nucleotide, resulting in an amino acid change from Ser to Phe. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO and MutationTaster not captured due to low reliability index).This variant was found in patients with MCL, idiopathic juxtafoveolar retinal telangiectasia, breast cancer, CLL, and CRC in germline and in tumor samples. However, co-segregation data were not available in these studies to establish causality of this variant in many studies. In one breast cancer family published in the literature, only the index patient had the variant while 3 affected sisters did not (Tommiska_2006), suggesting that this variant was not causative. The variant of interest was also found in 165/125148 control chromosomes at a frequency of 0.0013184. Specifically, in Finnish control population, MAF of this variant is 0.004548, which is greater than the estimated maximal expected frequency of a pathogenic ATM allele for AT (0.003953) or breast cancer (0.0005001), suggesting this variant is benign. In addition, multiple clinical laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant was classified as Likely Benign until additional information is available. - |
not specified Benign:6Other:1
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 17, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2017 | 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, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Ser333Phe variant was identified in 9 (1 homozygous) of 2296 proband chromosomes (frequency: 0.004) from Finnish and American individuals or families with non-BRCA1/2 breast cancer, breast cancer, early onset and familial CRC, and individuals undergoing radiation therapy, and was identified in 37 of8118 chromosomes from healthy (race matched controls) (Petereit 2013, Tommiska 2006, Teraoka 2001, Tanskanen 2015). Segregation studies in 1 family were negative, as the proband’s 3 affected sisters were non-carriers (Tommiska 2006). The variant was also identified in dbSNP (ID: rs28904919) “With Likely benign allele”, ClinVar (classified benign by Invitae, likely benign by GeneDx, Ambry Genetics and ARUP, and classification not provided by ITMI), Clinvitae (3x), Cosmic (2x in a hemangioblastoma and adnexal tumour) and not in MutDB and LOVD 3.0. The variant was identified in control databases in 439 of 276964 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 8 of 24024 chromosomes (freq: 0.0003), Other in 9 of 6462 chromosomes (freq: 0.001), Latino in 125 (1 homozygous) of 34380 chromosomes (freq: 0.004), European Non-Finnish in 209 of 126534 chromosomes (freq: 0.002), European Finnish in 88 of 25784 chromosomes (freq: 0.003), while not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ser333 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe 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, HumanSpliceFinder) 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. - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 20, 2022 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:3
| Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 25, 2020 | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 18, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2021 | This alteration is classified as likely 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 | clinical testing | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | The c.998C>T (p.Ser333Phe) missense variant has an allele frequency of 0.16%, (421/268,078 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.35%, (123/35,062 alleles) in the Latino / Admixed American subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 1 individual of the gnomAD v2.1.1 non-neuro dataset and in 1 individual older than 75 year, not affected from ataxia telangiectasia, from the Spanish ATM working group cancer cohort (BS2_Supporting, PMID: 33280026). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. However, the in silico protein effect prediction for this missense variant is inconclusive (no predictive criterion met). Therefore, the variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting (PMID: 33280026). - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 28, 2021 | - - |
Familial cancer of breast Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 24, 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]. - |
| Benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 22, 2023 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;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
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;N
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.61
.;P;P
Vest4
0.48, 0.54
MVP
MPC
0.38
ClinPred
T
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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