chr11-108247128-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.1065+1G>T variant causes a splice donor, intron 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
Consequence
NM_000051.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.1065+1G>T | splice_donor_variant, intron_variant | Intron 8 of 62 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:6
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This sequence change affects a donor splice site in intron 8 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ATM-related cancers (PMID: 28687971, 28888541, 32581083, 35264596). ClinVar contains an entry for this variant (Variation ID: 186470). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript [Splice AI: 0.97 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000186470 /PMID: 28687971). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1065+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 7 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was reported in 1/7051 Japanese female breast cancer cases, and was not detected in 11241 controls (Momozowa Y et al. Nat Commun 2018 10;9(1):4083). This alteration has also been reported in an individual diagnosed with lung cancer at age 53 and later diagnosed with pancreatic cancer at 62 (Slavin TP et al. Fam. Cancer, 2018 04;17:235-245). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). A published RNA study has also identified abnormal splicing associated with this variant (Bueno-Martínez E et al. J Pathol, 2022 Sep;258:83-101). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
This variant causes a G to T nucleotide substitution at the +1 position of intron 8 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA mini-gene assay showed that this variant disrupted splicing and resulted in no full length transcript (PMID: 35716007). This variant has been observed in an individual affected with breast cancer (PMID: 32581083) and an individual affected with lung and pancreatic cancer (PMID: 28687971). 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 Likely Pathogenic. -
Familial cancer of breast Pathogenic:2
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. -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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not provided Pathogenic:1
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28687971, 32581083, 35264596, 28888541) -
Malignant tumor of breast Pathogenic:1
Variant summary: ATM c.1065+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250980 control chromosomes. c.1065+1G>T has been reported in the literature in at-least one individual affected with lung cancer and Pancreatic ductal adenocarcinoma (example, Slavin_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at