rs17174393
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM3_StrongPVS1
This summary comes from the ClinGen Evidence Repository: The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a premature stop codon and nonsense mediated decay. The highest minor allele frequency in gnomAD v2.1.1 is 0.00003517 (4/113738) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID:26896183, 10817650, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274150/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8786+1G>A | splice_donor_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8786+1G>A | splice_donor_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251450Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD4 exome AF: 0.0000323 AC: 47AN: 1456446Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23AN XY: 724990
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:6
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 22, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 06, 2021 | Variant summary: ATM c.8786+1G>A 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: Four predict the variant abolishes a canonical 5' splicing donor site. Multiple publications, Laake_2000 and Stankovic_1998, functionally assessed the variant and found it to affect mRNA splicing. The variant was observed with an allele frequency of 1.2e-05 in 246218 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.2e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.8786+1G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Laake_2000, Stankovic_1998). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 19, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Oct 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 24, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | 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 may result in an absent or disrupted protein product. This variant is present in population databases (rs17174393, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). This variant is also known as IVS62+1G>A and c.8672del115. ClinVar contains an entry for this variant (Variation ID: 127463). Studies have shown that disruption of this splice site results in skipping of exon 60 and/or activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stankovic 1998, Garcia-Perez 2001, Reiman 2011); Observed in the heterozygous state in individuals with a personal or family history including lymphoma and colorectal cancer (Sutton 2015, AlDubayan 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS62+1G>A; This variant is associated with the following publications: (PMID: 8789452, 21445571, 25480502, 10330348, 9463314, 9443866, 10817650, 12552559, 11298136, 10980530, 8808599, 21792198, 8659541, 27479817, 29478780, 30338439, 30549301, 21459046, 25525159, 29625052, 31285527, 33436325, 30612635, 26681312, 31948886, 32853339, 26896183) - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen | Jan 25, 2024 | The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a premature stop codon and nonsense mediated decay. The highest minor allele frequency in gnomAD v2.1.1 is 0.00003517 (4/113738) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 26896183, 10817650, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong) - |
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. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 08, 2022 | This variant causes a G to A nucleotide substitution at the +1 position of intron 60 of the ATM gene. RNA studies have shown that this variant causes the skipping of exon 60 (also known as exon 62 in the literature) or the inclusion of the first 14 nucleotides of intron 60 in the RNA transcripts (PMID: 9463314, 10330348, 10980530, 11298136). Both aberrant transcripts are expected to create a frameshift and premature truncation and result in an absent or non-functional protein product. This variant (also known as IVS62+1G>A in the literature) has been reported in many individuals affected with ataxia telangiectasia (PMID: 9463314, 10330348, 10817650, 10980530, 11298136, 12552559, 21792198). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 2/53461 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991). This variant has also been identified in 4/251450 chromosomes 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 | Jan 10, 2023 | The c.8786+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after intron 59 of the ATM gene. This alteration has been detected in numerous individuals with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Li A and Swift M. 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; Schon K et al. Ann. Neurol. 2019 02;85(2):170-180). In addition, western blot analysis has shown that this alteration results in a truncated ATM protein product (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31). 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). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 15, 2021 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 01, 2022 | - - |
Malignant glioma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Feb 13, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at