rs878853535
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.6916_6917delAG(p.Leu2307CysfsTer65) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000616 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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.6916_6917delAG | p.Leu2307CysfsTer65 | frameshift_variant | Exon 47 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461856Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727228
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Variant summary: ATM c.6916_6917delAG (p.Leu2307CysfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251316 control chromosomes. c.6916_6917delAG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (example, Stankovic_1998, Thompson_2005, Carney_2012, Jackson_2016) and ATM-related cancers (example, Decker_2017, Arvai_2019). These data indicate that the variant is likely to be associated with disease. Six 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. -
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This sequence change creates a premature translational stop signal (p.Leu2307Cysfs*65) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9463314). ClinVar contains an entry for this variant (Variation ID: 236760). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:3
The c.6916_6917delAG pathogenic mutation, located in coding exon 46 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 6916 to 6917, causing a translational frameshift with a predicted alternate stop codon (p.L2307Cfs*65). This alteration has been reported in patients with ataxia-telangiectasia (Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62:334-45; Carney EF et al. J Immunol, 2012 Jul;189:261-8). It has also been reported in breast and/or ovarian cancer patients (Decker B et al. J Med Genet, 2017 11;54:732-741; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Arvai KJ et al. Hered Cancer Clin Pract, 2019 Jul;17:19). Of note, this alteration is also designated as "delta AG at nucleotide 9616" and "c.6914_6915delAG" in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
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This variant deletes 2 nucleotides 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. This variant is also known as c.6914_6915delAG in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 29522266, 33471991). This variant has also been reported in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 9463314, 22649200). 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 Pathogenic. -
Familial cancer of breast Pathogenic:3
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
not provided Pathogenic:2
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; Observed in individuals with breast cancer (Decker et al., 2017; Hauke et al., 2018; Lerner-Ellis et al., 2021); Co-observed, phase unclear, with a second ATM variant in individuals with features of ataxia telangiectasia (Carney et al., 2012; Jackson et al., 2016); This variant is associated with the following publications: (PMID: 28779002, 29522266, 34114234, 33804961, 31050087, 25614872, 33471991, 23807571, 32885271, 26896183, 9463314, 22649200, 31341520, 15928302) -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1Other:1
Variant interpreted as Pathogenic and reported on 04-18-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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Malignant tumor of breast Pathogenic:1
The ATM p.Leu2307Cysfs*65 variant was identified in 1 of 156 proband chromosomes (frequency: 0.006) from individuals or families with Ataxia-Telangiectasia in the British Isles (Stankovic 1996). The variant was also identified in dbSNP (ID: rs878853535) as “With Pathogenic allele”, ClinVar (2x as pathogenic by Invitae, GeneDx) and LOVD 3.0 (1x). The variant was not identified in the following databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6916_6917del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2307 and leads to a premature stop codon 65 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM associated disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at