rs587776549
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM3PM2_SupportingPVS1PM5_Supporting
This summary comes from the ClinGen Evidence Repository: The ATM c.3245_3247delinsTGAT (p.His1082LeufsTer14) variant is absent in the GnomAD cohort (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA298025/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 frameshift, missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.3245_3247delATCinsTGAT | p.His1082LeufsTer14 | frameshift_variant, missense_variant | Exon 22 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.3245_3247delATCinsTGAT | p.His1082LeufsTer14 | frameshift_variant, missense_variant | Exon 22 of 63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:5
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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The ATM c.3245_3247delinsTGAT (p.His1082LeufsTer14) variant is absent in the GnomAD cohort (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -
The variant causes a frameshift and creates a premature stop codon at position 14 of the new reading frame. The variant transcript is predicted to be degraded by nonsense-mediated decay or lead to a truncated protein. Loss of expression of one allele of ATM is a well-established mechanism of disease (Huang 2013, Podralska 2014). This variant has been reported in the literature in individuals with breast or prostate cancer (Vorechovsky 2996, Chen 1998, Hart 2016) and in individuals with ataxia-telangiectasia (Telatar 1998, Laake 1998, Laake 2000). This variant has an allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PVS1; PM3 -
Ataxia-telangiectasia syndrome Pathogenic:4
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
This sequence change creates a premature translational stop signal (p.His1082Leufs*14) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia, breast cancer, and/or prostate cancer (PMID: 8797579, 9443866, 9537233, 9781027, 10980530, 27084275). It is commonly reported in individuals of Norwegian ancestry (PMID: 9443866, 9781027, 10980530). ClinVar contains an entry for this variant (Variation ID: 3033). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: The ATM c.3245_3247delinsTGAT (p.His1082LeufsX14) 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. This variant is absent in 30972 control chromosomes (gnomAD). Multiple publications have cited the variant in affected A-T patients and has been indicated to be a Norwegian founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided Pathogenic:3Other:1
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; Observed in the heterozygous state in individuals with a personal history of ATM-related cancers (PMID: 8797579, 30067863, 31811167, 31391296); 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; This variant is associated with the following publications: (PMID: 26681312, 17540590, 15196260, 15942625, 9443866, 18321536, 9781027, 8797579, 9537233, 30067863, 27084275, 10817650, 31391296, 31811167, 30612635, 33763108, 32754152, 33144682, 29922827, 33436325, 32853339, 10980530) -
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Variant interpretted as Pathogenic and reported on 09-04-2019 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant replaces 3 nucleotides in exon 22 of the ATM gene with 4 new nucleotides, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ataxia-telangiectasia and is a recurrent mutation in the Norwegian population (PMID: 9443866, 9781027, 10980530). This variant has also been reported in individuals affected with breast cancer (PMID: 8797579, 9537233, 11104561, 31882575), prostate cancer (PMID: 27084275), and ovarian cancer (PMID: 31882575). 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. -
The c.3245_3247delATCinsTGAT pathogenic mutation, located in coding exon 21 of the ATM gene, results from the deletion of 3 nucleotides (ATC) and insertion of 4 nucleotides (TGAT) at positions 3245 to 3247, causing a translational frameshift with a predicted alternate stop codon (p.H1082Lfs*14). This mutation has been detected in both the homozygous and compound heterozygous state in multiple patients with ataxia-telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Stray-Pedersen A et al. Eur. J. Paediatr. Neurol. 2007 Nov;11:375-80). In addition, this mutation has been described as a Norwegian founder mutation and accounted for greater than 50% of pathogenic ATM alleles detected in one series of Norwegian A-T families (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46). This mutation was also detected in two individuals with histories of breast cancer and/or pilocytic astrocytoma (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1Other:1
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Variant interpreted as Pathogenic and reported on 11-21-2020 by 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. -
Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to Pathogenic:1
The c.3245_3247delATCinsTGAT (p.His1082Leufs*14) variant in the ATM gene creates a stop codon which is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant is absent from general population databases. Therefore, this c.3245_3247delATCinsTGAT (p.His1082Leufs*14) variant in the ATM gene is classified as pathogenic. -
ATM-related disorder Pathogenic:1
The ATM c.3245_3247delinsTGAT variant is predicted to result in a frameshift and premature protein termination (p.His1082Leufs*14). This variant has been reported in individuals with autosomal recessive ataxia telangiectasia (Table 2, referred to as 3245ATC>TGAT, Telatar et al. 1998. PubMed ID: 9443866). It has also been reported in individuals with breast cancer, pilocytic astrocytoma, and pancreatic cancer (Table 2, referred to as 3246insG, Vorechovský et al. 1996. PubMed ID: 8797579; Table S1, Susswein et al. 2015. PubMed ID: 26681312; eTable 3, Hu et al. 2018. PubMed ID: 29922827; Table 2, Brand et al. 2018. PubMed ID: 30067863). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://preview.ncbi.nlm.nih.gov/clinvar/variation/3033/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at