rs1060504292
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.8373C>A(p.Tyr2791*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
ATM
NM_000051.4 stop_gained
NM_000051.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.02
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108343326-C-A is Pathogenic according to our data. Variant chr11-108343326-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.8373C>A | p.Tyr2791* | stop_gained | 57/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gain variant c.8373C>A (p.Tyr2791Ter) in the ATM gene has been reported previously in compound heterozygous state in a patient affected with ataxia-telangiectasia (Verhagen MM. et al., 2012). Recent studies have confirmed that some variants of ATM in heterozygous state are associated with an increased risk of breast cancer development and a worse prognosis (Stucci LS. et al., 2021). However, association of p.Tyr2791Ter with breast cancer is currently not available in literature. The variant is novel in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 19, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2023 | This sequence change creates a premature translational stop signal (p.Tyr2791*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 9792409, 22213089). ClinVar contains an entry for this variant (Variation ID: 420016). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000420016). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 04, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 02, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 26, 2020 | This variant changes 1 nucleotide in exon 57 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 9792409, 22213089). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2022 | The p.Y2791* pathogenic mutation (also known as c.8373C>A), located in coding exon 56 of the ATM gene, results from a C to A substitution at nucleotide position 8373. This changes the amino acid from a tyrosine to a stop codon within coding exon 56. This variant has been identified likely in trans with an ATM pathogenic variant in an individual diagnosed with ataxia-telangiectasia (Broeks A et al. Hum Mutat, 1998;12:330-7; Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2016 | This variant is denoted ATM c.8373C>A at the cDNA level and p.Tyr2791Ter (Y2791X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the compound heterozygous state in two individuals with ataxia-telangiectasia (Broeks 1998, Verhagen 2012), and is considered pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at