rs786203201
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.901+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,597,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.901+1G>A | splice_donor_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.901+1G>A | splice_donor_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000163 AC: 4AN: 244780Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133194
GnomAD4 exome AF: 0.00000277 AC: 4AN: 1444986Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2AN XY: 719864
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2018 | Variant summary: ATM c.901+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: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 271632 control chromosomes (gnomAD). The variant, c.901+1G>A, has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Mitui_2003, Micol_2011, Du_2008) and one ovarian cancer (Crawford_2017) where it was found together with the pathogenic variant PALB2 c.2167_2168delAT (p.Met723fsX21). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change affects a donor splice site in intron 7 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 (rs748840480, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with ATM-related conditions (PMID: 8321536, 12815592, 21665257, 28281021, 31206626). ClinVar contains an entry for this variant (Variation ID: 186761). Studies have shown that disruption of this splice site results in skipping of exon 7 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 31, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2023 | The c.901+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the ATM gene. This alteration was identified in conjunction with a truncating ATM mutation in an individual diagnosed with ataxia-telangiectasia (Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50). This alteration was also reported in a male diagnosed with breast cancer and an individual diagnosed with ovarian cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586; Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163(2):383-390). This alteration is also known as IVS9+1G>A in published literature. 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). 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 a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 13, 2022 | This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the ATM gene. This variant is also known as IVS9+1G>A in the literature. Functional studies using patient-derived lymphoblastoid cells showed skipping of exon 7 and premature protein termination (PMID: 18321536). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 12815592, 18321536). This variant also has been reported in an individual affected with male breast cancer (PMID: 28008555). This variant has been identified in 5/276176 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 | curation | Sema4, Sema4 | Nov 24, 2021 | - - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 11, 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;C0346153:Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at