chr11-108247085-CAAAG-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.1027_1030delGAAA(p.Glu343IlefsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.1027_1030delGAAA | p.Glu343IlefsTer2 | frameshift_variant | Exon 8 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151966Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251144Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135754
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461536Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727072
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151966Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74204
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:5
This sequence change creates a premature translational stop signal (p.Glu343Ilefs*2) 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). This variant is present in population databases (rs587780612, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559, 18502988, 21792198, 22213089). This variant is also known as 1024delAAAG, 1027_1030delAAAG, and 1027del4. ClinVar contains an entry for this variant (Variation ID: 135731). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: The ATM c.1027_1030delGAAA (p.Glu343Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp393X, p.Gln1017X, p.Arg1466X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121026 control chromosomes but has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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not provided Pathogenic:5
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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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Published functional studies demonstrate reduced levels of protein expression (Becker-Catania et al., 2000); This variant is associated with the following publications: (PMID: 22213089, 19535770, 18502988, 26270727, 28126470, 17985259, 28152038, 10330348, 12552559, 10817650, 21792198, 28873162, 30067863, 30267352, 29506128, 30716324, 29288088, 30980208, 30338439, 26689913, 31871297, 29625052, 29922827, 33858029, 10873394) -
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Additionally, the variant was found in at least one symptomatic patient, and found in general population data at a frequency that is consistent with pathogenicity. -
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Hereditary cancer-predisposing syndrome Pathogenic:4
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This variant deletes 4 nucleotides in exon 8 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. To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been reported in individuals with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559) with several confirmed in the compound heterozygous state (PMID: 10873394, 21792198, 22213089). This variant has been identified in 8/251144 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. -
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The c.1027_1030delGAAA pathogenic mutation, located in coding exon 7 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 1027 to 1030, causing a translational frameshift with a predicted alternate stop codon (p.E343Ifs*2). This mutation has been reported in numerous patients with classic Ataxia-Telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33; Buzin C et al. Hum. Mutat. 2003 Feb;21(2):123-31) and in an individual from a hereditary breast and ovarian cancer cohort (Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). ATM protein expression was found to be entirely absent in one A-T individual with this alteration in conjunction with another ATM mutation (Reiman A et al. Br. J. Cancer. 2011 Aug;105(4):586-91). Of note, this alteration is also designated as 1024delAAAG, c.1024_1027delAAAG, and 1027_1030delAAAG 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. -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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ATM-related disorder Pathogenic:1
The ATM c.1027_1030delGAAA variant is predicted to result in a frameshift and premature protein termination (p.Glu343Ilefs*2). This variant has previously been reported to be causative for autosomal recessive ataxia telangiectasia (see for example, Teraoka et al. 1999. PubMed ID: 10330348, reported as 1024del; Verhagen et al. 2009. PubMed ID: 19535770). This variant is also reported as pathogenic in an individual with adenocarcinoma of the gastroesophageal junction (Table 1. El Jabbour et al. 2022. PubMed ID: 35078243). This variant is reported in 0.050% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135731/?new_evidence=true). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at