chr11-108272782-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.3214G>T(p.Glu1072Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,722 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1072E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 stop_gained
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.3214G>T | p.Glu1072Ter | stop_gained | 22/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.3214G>T | p.Glu1072Ter | stop_gained | 22/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251360Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461566Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727100
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Glu1072*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9443866, 22585167). ClinVar contains an entry for this variant (Variation ID: 407699). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2022 | Variant summary: ATM c.3214G>T (p.Glu1072X) 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 allele was found at a frequency of 4e-06 in 251360 control chromosomes. c.3214G>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Soukupova_2011, Mitui_2005, Jackson_2016). 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2022 | Nonsense 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 the heterozygous state in individuals with pancreatic cancer (Roberts et al., 2012; Hutchings et al., 2019); This variant is associated with the following publications: (PMID: 8808599, 22585167, 25525159, 9443866, 30579816, 21833744, 31285527, 16266405) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 18, 2020 | 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). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 19, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 13, 2023 | - - |
Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Nov 13, 2018 | The c.3214G>T (p.Glu1072*) variant in exon 22 of the ATM gene introduces a premature termination codon and is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been observed in at least two patients with ataxia telangiectasia for which the second allele is both known to be in trans, and is a pathogenic variant (PMID 21833744 and 16266405). This variant is has been observed only once in a heterozygous state in a large population database (gnomAD). Therefore, the c.3214G>T (p.Glu1072*) variant in the ATM gene is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2021 | The p.E1072* pathogenic mutation (also known as c.3214G>T), located in coding exon 21 of the ATM gene, results from a G to T substitution at nucleotide position 3214. This changes the amino acid from a glutamic acid to a stop codon within coding exon 21. This mutation has been detected in conjunction with a second ATM alteration in numerous patients with Ataxia-Telangiectasia (A-T) (Wright J et al. Am. J. Hum. Genet., 1996 Oct;59:839-46; Telatar M et al. Am. J. Hum. Genet., 1998 Jan;62:86-97; Teraoka SN et al. Am J Hum Genet, 1999 Jun;64:1617-31; Mitui M et al. Ann. Hum. Genet., 2005 Nov;69:657-64; Soukupova J et al. Neuromolecular Med., 2011 Sep;13:204-11; Paucar M et al. Parkinsonism Relat Disord, 2019 05;62:253-255). This mutation has also been detected in patients with pancreatic and ovarian cancer (Roberts NJ et al. Cancer Discov, 2012 Jan;2:41-6; Harter P et al. PLoS One, 2017 Oct;12:e0186043; Hutchings D et al. Mod Pathol, 2019 12;32:1806-1813). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at