rs864622758
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):āc.280A>Gā(p.Met94Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 6.77
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 -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.32341826).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.280A>G | p.Met94Val | missense_variant | 4/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.280A>G | p.Met94Val | missense_variant | 4/63 | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251076Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135728
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461542Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727048
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74336
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2023 | Variant summary: ATM c.280A>G (p.Met94Val) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair (IPR021668) 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 4e-06 in 251076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.280A>G has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome and Neuroblastoma (Tung_2015, Yurgelun_2015, Zhang_2015) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 18, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the ATM protein (p.Met94Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 221134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 04, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | This variant is associated with the following publications: (PMID: 25980754, 25186627) - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 22, 2023 | Criteria applied: PM2_SUP,BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 28, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 19, 2023 | This missense variant replaces methionine with valine at codon 94 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 (PMID: 25980754). This variant has been identified in 1/251076 chromosomes 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 | Ambry Genetics | Oct 22, 2023 | The p.M94V variant (also known as c.280A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 280. The methionine at codon 94 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with neuroblastoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T;.;T;T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;.;.;.;.;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;D;.;N;.;.;.;.;.
REVEL
Benign
Sift
Benign
T;T;D;.;T;.;.;.;.;.
Sift4G
Uncertain
D;T;T;T;T;.;.;.;T;T
Polyphen
0.52, 0.64
.;P;.;.;P;P;P;P;P;.
Vest4
0.61, 0.64, 0.63, 0.65
MutPred
Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);Gain of methylation at K93 (P = 0.0168);
MVP
MPC
0.17
ClinPred
D
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