rs773570504
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.6908dup(p.Glu2304GlyfsTer69) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A2301A) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6908dup | p.Glu2304GlyfsTer69 | frameshift_variant | 47/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6908dup | p.Glu2304GlyfsTer69 | frameshift_variant | 47/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151818Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251246Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135796
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727198
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151818Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74130
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in individuals with familial breast cancer (Pylkas et al., 2007; Allinen et al., 2002; Nurmi et al., 2019); Also known as c.6903insA; This variant is associated with the following publications: (PMID: 30549301, 30927251, 19535770, 22213089, 21792198, 11897822, 29922827, 23807571, 25614872, 36551643, 37284046, 17166884, 31921190) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 01, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 30, 2024 | This variant is considered pathogenic. This variant creates a frameshift 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 | Jan 21, 2020 | This variant inserts 1 nucleotide in exon 47 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant (also known as 6903insA in the literature) has been reported in individuals affected with ataxia telangiectasia (PMID: 11897822, 1935770, 21792198) and breast cancer (PMID: 11897822, 30927251). This variant has also been identified in 4/251246 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 | Jul 20, 2020 | The c.6908dupA pathogenic mutation, located in coding exon 46 of the ATM gene, results from a duplication of A at nucleotide position 6908, causing a translational frameshift with a predicted alternate stop codon (p.E2304Gfs*69). This pathogenic mutation has been observed in multiple individuals with ataxia telangiectasia along with another ATM alteration (Verhagen MM et al. Neurology 2009 Aug; 73(6):430-7; Schon K et al. Ann. Neurol., 2019 02;85:170-180; Mandola AB et al. Front Immunol, 2019 Dec;10:2940). This mutation has also been reported in multiple patients with a personal and/or family history of breast cancer (Allinen M et al. J. Med. Genet. 2002 Mar; 39(3):192-6; Pylkäs K et al. Carcinogenesis, 2007 May;28:1040-5; Nurmi A et al. Int. J. Cancer, 2019 11;145:2692-2700). Of note, this alteration is also designated as 6903insA in published literature. 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. - |
Ataxia-telangiectasia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 453647). This variant is also known as 6903insA. This premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 11897822, 19535770, 30549301). This variant is present in population databases (rs773570504, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu2304Glyfs*69) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at