chr11-108353881-G-C
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.8786+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ATM
NM_000051.4 splice_donor
NM_000051.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 10.0
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 22 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-108353881-G-C is Pathogenic according to our data. Variant chr11-108353881-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108353881-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8786+1G>C | splice_donor_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8786+1G>C | splice_donor_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 05, 2024 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Ataxia-telangiectasia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change affects a donor splice site in intron 60 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 187060). Studies have shown that disruption of this splice site results in skipping of exon 60 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the ATM protein in which other variant(s) (p.Asp2913Tyr) have been determined to be pathogenic (PMID: 21665257, 22071889, 31050087, 33436325). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with ATM-related cancers referred for genetic testing at GeneDx and in published literature (Abida et al., 2017; Mandelker et al., 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26618343, 28873162, 28825054, 30287823) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2022 | The c.8786+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 59 of the ATM gene. This alteration has been identified in an individual with prostate cancer (Abida W et al. JCO Precis Oncol. 2017 Jul;2017). In addition, a different pathogenic mutation at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous individuals diagnosed with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Laake K et al. Hum. Mutat. 2000 Sep;16:232-46). RNA studies showed abnormal splicing in individuals with the c.8786+1G>C alteration (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at