rs587781831
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.381del(p.Val128Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T127T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ATM
NM_000051.4 frameshift
NM_000051.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.625
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-108235718-CA-C is Pathogenic according to our data. Variant chr11-108235718-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108235718-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.381del | p.Val128Ter | frameshift_variant | 5/63 | ENST00000675843.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.381del | p.Val128Ter | frameshift_variant | 5/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251238Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135790
GnomAD3 exomes
AF:
AC:
1
AN:
251238
Hom.:
AF XY:
AC XY:
0
AN XY:
135790
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459792Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726396
GnomAD4 exome
AF:
AC:
2
AN:
1459792
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
726396
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2018 | The ATM c.381delA (p.Val128Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Val128Ter variant has been found in at least six individuals with ataxia-telangiectasia, all in a compound heterozygous state (Babaei et al. 2005; Mitui et al. 2005; Quarantelli et al. 2013; Podralska et al. 2014). Control data are not available for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the potential impact of frameshift variants, the p.Val128Ter variant is classified as pathogenic for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | May 08, 2023 | - - |
| 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 | Aug 15, 2022 | Variant summary: ATM c.381delA (p.Val128X) 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 251238 control chromosomes. c.381delA has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (examples: Broccoletti_2011, Micol_2011, Mitui_2005, Al-Muhaizea_2022, etc). Experimental evidence evaluating an impact on protein function, demonstrated the variant to result in an overall reduced ATM protein level, mRNA level and cell survival after exposure to ionizing radiation (Fernet_2004). 16 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | This sequence change creates a premature translational stop signal (p.Val128*) 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 (rs587781831, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 15843990, 16266405, 25502423, 25614872). This variant is also known as c.380delA and c.381_381delA. ClinVar contains an entry for this variant (Variation ID: 141546). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 02, 2021 | - - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2023 | Observed with a second ATM variant in individuals with ataxia telangiectasia (Babaei et al., 2005; Broccoletti et al., 2011); Observed in the heterozygous state in individuals with ATM-related cancers referred for genetic testing at GeneDx and in published literature (Siraj et al., 2017); 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); This variant is associated with the following publications: (PMID: 10330348, 26662178, 29922827, 16266405, 25502423, 15390180, 20840352, 15843990, 14970866, 28975465, 28779002, 31850668, 21665257, 22763152, 10425038, 11839094, 33779842) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 13, 2017 | The c.381delA variant has been previously reported in association with ataxia telangiectasia in multiple unrelated families (Mitui 2005, and Babaei 2005). The c.381delA variant creates a frameshift in the ATM protein at codon 128 in exon 5 which results in a premature termination codon and is predicted to result in a truncated or absent protein product. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP) , and the Exome Aggregation Consortium (ExAC) browser but has been reported to ClinVar (Variation ID: 141546). Based on these observations, the c.381delA variant has been classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 06, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Familial cancer of breast Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 20, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 09, 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 | Aug 24, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 09, 2023 | A known pathogenic mutation was detected in the ATM gene(p.Val128Ter). This sequence change creates a premature translational stop signal (p.Val128*) 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 (rs587781831, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 15843990, 16266405, 25502423, 25614872). This variant is also known as c.380delA and c.381_381delA. ClinVar contains an entry for this variant (Variation ID: 141546). For these reasons, this variant has been classified as Pathogenic. Pathogenic germline variants in the ATM gene are associated to increased breast cancer risk and further ATM-related malignancies. The cancer risk of individuals heterozygous for an ATM pathogenic variant is approximately four times that of the general population. Cancer risk probably depends on multiple factors including tumor type, age at cancer onset, and whether the type of variant (PMID: 20301790, OMIM® 114480). According to NCCN guidelines (version 3.2023), pathogenic or likely pathogenic variants in this gene are associated with 6% by age 50 years and 33% by age 80 years lifetime risk of breast cancer. The risk increases with increasing number of relatives affected with breast cancer. Hereditary predisposition to cancer due to pathogenic variants in the ATM gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. In addition, ATM, ATM serine/threonine kinase, is a member of the serine-threonine kinase family and coordinates cellular responses to DNA damage through activation of distinct DNA repair and signaling pathways (PMID: 22079189). ATM germline mutations are associated also with ataxia telangiectasia, an autosomal recessive disorder (OMIM®: 208900, PMID: 27283171). Furthermore, Roberts et al., 2012 published a study indicating that ATM variants play an important role in familial pancreatic cancer predisposition (PMID: 22585167: PMID: 34529012). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 30, 2024 | Criteria applied: PVS1,PM3_STR,PM2_SUP - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2021 | The c.381delA pathogenic mutation (also known as p.V128*), located in coding exon 4 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 381. This changes the amino acid from a valine to a stop codon within coding exon 4. This mutation has been reported in multiple ataxia-telangiectasia (A-T) families to date (Babaei M et al. Hum. Genet. 2005 Jul;117(2-3):101-6; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11) as well as an in a high-risk melanoma cohort (Stolarova L et al. Biomedicines, 2020 Oct;8). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 07, 2022 | This variant deletes 1 nucleotide in exon 5 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. This variant has been reported in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 10330348, 10425038, 11839094, 15843990, 20840352). This variant has been identified in 1/251238 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. - |
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 | Feb 01, 2019 | The c.381delA (p.Val128*) variant in the ATM gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has an extremely low frequency in large databases of genetic variation in the general population. This variant has been reported in multiple patients with Ataxia-telangiectasia (PMID 10425038, 15843990, 16266405 and 25614872). Experimental studies in heterozygous cell lines suggested that this variant leads to reduced ATM protein expression following exposure to radiation (PMID 14970866). Bi-allelic variants in the ATM gene are associated with Ataxia-telangiectasia (MIM #208900). Therefore, the c.381delA (p.Val128*) variant in the ATM gene is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at