11-108289761-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.4396C>T(p.Arg1466*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,176 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
ATM
NM_000051.4 stop_gained
NM_000051.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.87
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-108289761-C-T is Pathogenic according to our data. Variant chr11-108289761-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 236716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.4396C>T | p.Arg1466* | stop_gained | 29/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251064Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135696
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1461176Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726896
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 19, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg1466*) 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 (rs730881369, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10425038, 12552559, 19691550, 22213089, 22527104, 26439923). 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: 236716). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2024 | Observed in the heterozygous state in an individual with a personal and family history of breast cancer (PMID: 22527104); 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 a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 34326862, 34797032, 36305856, 29922827, 10425038, 12552559, 26439923, 18431795, 19691550, 11857346, 22213089, 32885271, 25525159, 22527104) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 13, 2021 | This nonsense variant causes the premature termination of ATM protein synthesis. In addition, it has been reported in individuals affected with ataxia-telangiectasia in the published literature (PMIDs: 26439923 (2015), 22527104 (2012), 22213089 (2011), 19691550 (2009), 12552559 (2003), and 10425038 (1999)). Based on the available information, this variant is classified as pathogenic. - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 24, 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 | Dec 11, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant changes 1 nucleotide in exon 29 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 4/251064 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 | Feb 01, 2024 | The p.R1466* pathogenic mutation (also known as c.4396C>T), located in coding exon 28 of the ATM gene, results from a C to T substitution at nucleotide position 4396. This changes the amino acid from an arginine to a stop codon within coding exon 28. This pathogenic mutation has been observed in numerous individuals with ataxia-telangiectasia (Castellví-Bel S et al. Hum. Mutat. 1999;14:156-62; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72:10-8; Chessa L et al. Ann. Hum. Genet. 2009 Sep;73:532-9; Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71; Chen Z et al. PLoS ONE, 2015 Oct;10:e0139738). It was also reported in an individual with bilateral breast cancer and a family history of breast cancer (Snape K et al. Breast Cancer Res. Treat. 2012 Jul;134:429-33) as well as in an individual diagnosed with breast carcinoma in situ at age 72 (Eliade M et al. Oncotarget, 2017 Jan;8:1957-1971). 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;C0346153:Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Arg1466* variant was identified in 10 of 1670 proband chromosomes (frequency: 0.006) from individuals or families with ataxia-telangiectasia or breast cancer (Buzin 2003, CastellvíBel 1999, Chen 2015, Chessa 2009, Eliade 2017, Verhagen 2011). The variant was also identified in dbSNP (ID: rs730881369) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and four other submitters), and in LOVD 3.0 (2x). The variant was identified in control databases in 4 of 245856 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33544 chromosomes (freq: 0.00003), European in 1 of 111498 chromosomes (freq: 0.000009), and South Asian in 2 of 30750 chromosomes (freq: 0.00007); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The c.4396C>T variant leads to a premature stop codon at position 1466, 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 ATM-associated cancer susceptibility 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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