chr11-108365152-C-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_000051.4(ATM):c.8921C>T(p.Pro2974Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000979 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2974Q) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 3.67
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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.05563709).
BP6
Variant 11-108365152-C-T is Benign according to our data. Variant chr11-108365152-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135787.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Benign=2, Likely_benign=2}. Variant chr11-108365152-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000101 (148/1461880) while in subpopulation EAS AF= 0.00254 (101/39698). AF 95% confidence interval is 0.00214. There are 0 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.8921C>T | p.Pro2974Leu | missense_variant | 62/63 | ENST00000675843.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.8921C>T | p.Pro2974Leu | missense_variant | 62/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251398Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135868
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GnomAD4 exome AF: 0.000101 AC: 148AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000949 AC XY: 69AN XY: 727238
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:13Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 09, 2016 | In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 32601921 (2020), 30287823 (2018), 23555315 (2013), 24326041 (2013)), colorectal cancer (PMID: 33309985 (2020)), and pancreatic cancer (PMID: 32980694 (2020), 28726808 (2018)). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), 32601921 (2020), 30287823 (2018), 28652578 (2017)). Functional studies have reported that this variant has a damaging effect on ATM protein function (PMID: 12511424 (2003), 31160347 (2019)). The frequency of this variant in the general population, 0.001 (4/3816 chromosomes in Korean subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 | GeneDx | Nov 02, 2023 | Observed in individuals with breast, ovarian, colorectal, biliary, or pancreatic cancer, but also in unaffected controls (PMID: 24326041, 28726808, 29522266, 32091409, 33309985, 34326862, 36243179); Published functional studies demonstrate mRNA expression levels equivalent to wild type, lower repair efficiency after DNA damage, partial loss of homologous recombination repair activity, and reduction in phosphorylation activity (PMID: 12511424, 31160347); 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: 24326041, 23636326, 28652578, 32566746, 32601921, 33309985, 14628072, 12969974, 12511424, 28873162, 26991699, 23555315, 1806608, 16941484, 29522266, 31160347, 30287823, 26689913, 20232390, 34426522, 11185744, 10923033, 15696190, 32980694, 32091409, 28726808, 33471991, 23532176, 34326862, 36243179) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | ATM: PS3:Supporting, BP4 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 02, 2023 | BP4 - |
Ataxia-telangiectasia syndrome Uncertain:3Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 28, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 25, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2024 | 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 | curation | Sema4, Sema4 | Jun 03, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 23, 2016 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 27, 2024 | Variant summary: ATM c.8921C>T (p.Pro2974Leu) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 1632190 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0044 (in the jMorp database). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. In addition, this variant has also been reported in 2/2559 African American women who were older than age 70 and cancer free (in the FLOSSIES database). c.8921C>T has been reported in the literature in individuals affected with Breast Cancer (BrC) and other tumor phenotypes. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. Two recent case-control association studies involving breast cancer patients and controls of Japanese ancestry found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of this study classified the variant as benign (Momozawa_2018, Fujita_2020). However, another recent case-control association study, involving breast cancer patients and controls of Chinese ancestry (Guo_2019), found an enrichment of this variant in cases, suggesting this variant could be associated with a risk for late onset BrC, though no statistically significant enrichment of this variant was observed in early-onset BrC patients (<45 years old). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect suggest a partial loss of ATM activity and a dominant-negative effect of the repair ability of this p.Pro2974Leu variant in ATM has been proposed (Oguchi_2003, Guo_2019). Due to a lack of complete loss of activity, the correlation of these findings to the in-vivo mechanism of disease remains unclear. The following publications have been ascertained in the context of this evaluation (PMID: 33309985, 32601921, 31160347, 23555315, 24326041, 15696190, 26689913, 30287823, 12511424, 20232390, 12969974, 28652578). ClinVar contains an entry for this variant (Variation ID: 135787). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 14, 2022 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Pro2974Leu variant was identified in 1 of 14 proband chromosomes (frequency: 0.07) from individuals or families with acute lymphoid and myeloid leukemia with mixed lineage leukemia (MLL) (Oguchi 2003). The variant was also identified in dbSNP (ID: rs139379666) as “With Uncertain significance allele”, in the ClinVar database as uncertain significance by Invitae, GeneDx, and Ambry Genetics. The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. In addition, the variant was identified in control databases in 23 of 277148 chromosomes at a frequency of 0.00008 (Genome Aggregation Consortium Feb 27, 2017); in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 1 of 4402 African American alleles (frequency: 0.0002). In one functional study, the p.Pro2974Leu variant in the PI-3 kinase domain of the ATM gene was identified in one patient with myeloid leukemia with a normal level expression of the ATM protein. The variant leads to a change in the secondary structure of the ATM protein, namely, loss of random coil between alpha helices. In vitro kinase studies showed that 8921T was defective in mediating p53-Ser15 phosphorylation. Thus, this change in the secondary structure of the PI-3 kinase domain may disrupt its enzymatic function. Expression of 8921T ATM in AT fibroblasts sowed only partial rescue of the radiosensitive phenotype. In addition, its expression in U2OS cells showed an interfering effect with the normal function of ATM. This finding strongly suggests pathogenicity. Furthermore, segregation analysis revealed the father of the affected child to be heterozygous for the variant, thus excluding the possibility that the variant arising de novo in the patient. As of the writing of this study, the father remains disease free indicating a low penetrance. However, environmental factors such as exposure to top II inhibitors during development played a role in the development of MLL leukemia in this patient. The p.Pro2974 residue is conserved in mammals but not in more distantly related organisms 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Phosphatidylinositol 3-/4-kinase, catalytic domain Armadillo-type fold functional domain(s) increasing the likelihood that it may 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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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