11-108365208-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.8977C>T(p.Arg2993*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000051.4 stop_gained
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 rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.8977C>T | p.Arg2993* | stop_gained | Exon 62 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251400Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135866
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727242
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6
The ATM p.Arg2993X variant was identified in 10 (1 homozygous) of 972 proband chromosomes (frequency: 0.01) from Italian, Spanish and British individuals or families with BRCA1/2 negative breast cancer, Ataxia-Telangiectasia or CLL; and was not identified in 2196 chromosomes from healthy individuals (Chessa 2009, Grana 2011, Magliozzi 2006 , Skowronska 2012, Mitui 2003). The variant was also identified in dbSNP (ID: rs770641163) “With Pathogenic allele”, ClinVar (classified as likely pathogenic by Counsyl,Dr. Peter K. Rogan Lab,Western University and pathogenic by Ambry Genetics, Invitae and GeneDx), Clinvitae (4x), and Cosmic (7x in thyroid, breast, large intestine and endometrial carcinomas and lymphoid neoplasm) and was not identified in the COGR. The variant was identified in control databases in 3 of 246160 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 3 of 111620 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Arg2993X variant leads to a premature stop codon at position 2993 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in Ataxia-Telangiectasia and is the type of variant expected to cause the disorder; the relative risk for hereditary breast and ovarian cancer is not certain but may lead to increased risk of breast cancer. In addition, this variant occurs within 50 base pairs of the penultimate exon junction of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -
ATM: PVS1:Strong, PM2, PM3, PS3:Supporting, PS4:Supporting -
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This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) In multiple individuals with ataxia-telangiectasia, this variant has been seen with a single recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23774824) -
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 64 amino acids are lost, and other loss-of-function variants have been reported downstream in ClinVar; Observed in both the homozygous and compound heterozygous states in multiple unrelated patients with ataxia telangiectasia (Li 2000, Sun 2002, Mitui 2003, Claret Teruel 2005, Magliozzi 2006, Chessa 2009, Carranza 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23774824, 21445571, 24682267, 10817650, 25862857, 16238588, 19691550, 17124347, 26898890, 9043869, 21933854, 12673797, 17968022, 15498871, 19770270, 23322442, 24951259, 25344691, 12815592, 12072877, 26886021, 27664052, 29489040, 30339652, 28779002, 29915322, 31159747, 31549213, 30772474, 29625052, 33436325, 31285527, 23532176, 35245693, 35078243, 34949663) -
Ataxia-telangiectasia syndrome Pathogenic:5
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Variant summary: The ATM c.8977C>T (p.Arg2993X) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121398 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been reported in publications in affected individuals both in the homozygous and compound heterozygous state. 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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This sequence change creates a premature translational stop signal (p.Arg2993*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the ATM protein. This variant is present in population databases (rs770641163, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with chronic lymphocytic leukemia and ataxia-telangiectasia (A-T) (PMID: 12815592, 16238588, 17124347, 20840352, 21933854, 23322442). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 186330). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 23774824). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:3
The p.R2993* pathogenic mutation (also known as c.8977C>T), located in coding exon 61 of the ATM gene, results from a C to T substitution at nucleotide position 8977. This changes the amino acid from an arginine to a stop codon within coding exon 61. This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 64 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been identified in multiple patients with ataxia-telangiectasia (A-T) from various ethnic backgrounds (Vorechovský I et al. Eur. J. Hum. Genet. 1996;4:352-5; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Claret Teruel G et al. Pediatr Allergy Immunol, 2005 Nov;16:615-8; Magliozzi M et al. Dis. Markers 2006;22:257-64; Broccoletti T et al. Eur J Neurol, 2011 Apr;18:564-70; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94; Balta G et al. J Pediatr Hematol Oncol, 2019 04;41:243-246; Suspitsin E et al. Eur J Med Genet, 2020 Jan;63:103630). In one study, the authors reported that ATM was not expressed in the cell line generated from a Spanish A-T patient who was compound heterozygous for this mutation and a second truncating mutation (Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
This variant changes 1 nucleotide in exon 62 of the ATM gene, creating a premature translation stop signal in the penultimate coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein lacking the C-terminal TP53 binding domain and FATC domain (PMID: 19779456). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). This variant has also been reported in the homozygous state or compound heterozygous state with a pathogenic variant in the same gene in individuals affected with autosomal recessive ataxia telangiectasia (PMID: 12815592, 16238588, 17124347, 20840352, 23322442, 30772474). This variant has been identified in 3/251400 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. -
This nonsense variant is a substitution of one nucleotide at position 8977 of the ATM protein, resulting in the creation of a stop codon at position 2993 of the ATM protein. The resulting protein is truncated and inactive. The mutation database ClinVar contains entries for this variant (Variation ID: 186330). -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Breast cancer, susceptibility to Pathogenic:1
This nonsense variant found in exon 62 of 63 is predicted to result in loss of normal protein function. This variant has been previously reported in the homozygous and compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMID: 9043869, 12815592, 23322442, 17124347, 16238588, 20840352), and in the heterozygous state in individuals as part of cancer predisposition studies ( PMID: 21933854, 31159747, 28779002). This variant has been reported in the ClinVar database (Variation ID: 186330). Functional studies performed on cells derived from a patient with the c.8977C>T (p.Arg2993Ter) variant in the homozygous state and affected with Ataxia Telangiectasia showed loss of kinase activity (PMID: 23774824). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251400) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.8977C>T (p.Arg2993Ter) variant on protein function. Based on the available evidence, the c.8977C>T (p.Arg2993Ter) variant is classified as Pathogenic. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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Koolen-de Vries syndrome Pathogenic:1
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Hereditary breast ovarian cancer syndrome Pathogenic:1
Sequenced patient with familial breast cancer -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at