rs1800558
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000051.4(ATM):c.8968G>A(p.Glu2990Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 4.44
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 Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.20277873).
BP6
Variant 11-108365199-G-A is Benign according to our data. Variant chr11-108365199-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127466.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7, not_provided=1}. Variant chr11-108365199-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.8968G>A | p.Glu2990Lys | missense_variant | 62/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.8968G>A | p.Glu2990Lys | missense_variant | 62/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251400Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135868
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727244
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GnomAD4 genome 0.0000394 AC: 6AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 31, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2023 | This missense variant replaces glutamic acid with lysine at codon 2990 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps, together with the pathogenic co-variant MSH6 c.3802-14_3809del (PMID: 25980754). This variant has also been reported in an individual affected with prostate cancer (PMID: 29368341) as well as in three women older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/). In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). This variant has been identified in 12/282800 chromosomes (11/10368 Ashkenazi Jewish chromosomes, 0.11%) 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 19, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2023 | The p.E2990K variant (also known as c.8968G>A), located in coding exon 61 of the ATM gene, results from a G to A substitution at nucleotide position 8968. The glutamic acid at codon 2990 is replaced by lysine, an amino acid with similar properties. This alteration was seen in 1/150 unselected patients with recurrent or metastatic prostate cancer; this individual also had an alteration in BARD1 (Isaacsson Velho P et al. Prostate, 2018 04;78:401-407). Additionally, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 25779943, 25980754, 28873162, 29368341, 28652578, 31970404, 33471991, 23532176, 29684080, 34326862, 35085662, 36845387, 32885271) - |
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.Glu2990Lys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.000397) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs1800558) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Color Genomics), and Clinvitae (3x as uncertain significance), databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0 databases. The variant was identified in control databases in 13 of 277140 chromosomes at a frequency of 0.000047 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 2 of 126628 chromosomes (freq: 0.000016), and Ashkenazi Jewish in 11 of 10150 chromosomes (freq: 0.001084), while the variant was not observed in the African, Other, Latino, East Asian, European (Finnish), and South Asian populations. The variant was identified with a co-occurring pathogenic BRCA1 variant (p.Gln1756ProfsX74), increasing the likelihood that the p.Glu2990Lys variant does not have clinical significance. The p.Glu2990Lys residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 24, 2023 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2023 | Variant summary: ATM c.8968G>A (p.Glu2990Lys) results in a conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.8968G>A has been reported in the literature in individuals affected with various cancers: Breast cancer (Dorling_2021, Lu_2015), Ovarian cancer (Lu_2015), Leukemia (Lu_2015), Astrocytoma (Muskens_2020), colon cancer (Yurgelun_2015), prostate cancer (Isaacsson Velho_2018), and gastrointestinal cancer (Bhai_2022). However, the variant was also found in 3/7325 European American women over the age of 70 with no history of cancer (FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least one co-occurrence with another pathogenic variant(s) has been reported (BRCA2 c.5946delT, p.Ser1982Argfs*22), providing supporting evidence for a benign role (Bhai_2022). 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: 25980754, 26689913, 29368341, 33471991, 31970404, 34326862). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six classified the variant as uncertain significance, and one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant classified as Likely benign and reported on 02-25-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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
Benign
T;.
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Gain of ubiquitination at E2990 (P = 0.0104);Gain of ubiquitination at E2990 (P = 0.0104);
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