11-108244912-CT-C
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1PM3_StrongPM5_Supporting
This summary comes from the ClinGen Evidence Repository: The c.790delT (p.Y264Ifs*12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001763 (2/113450 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID:12815592, 9887333, 26896183, 22213089). In summary, this variant meets the criteria to be classified as a pathogenic variant for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3_strong, PM5_supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA166283/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 frameshift
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 13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.790delT | p.Tyr264IlefsTer12 | frameshift_variant | Exon 7 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.790delT | p.Tyr264IlefsTer12 | frameshift_variant | Exon 7 of 63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000797 AC: 2AN: 251032 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461418Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727028 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:6
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Criteria applied: PVS1,PM3_STR,PM2_SUP -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
The c.790delT (p.Y264Ifs*12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001763 (2/113450 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID: 12815592, 9887333, 26896183, 22213089). In summary, this variant meets the criteria to be classified as a pathogenic variant for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3_strong, PM5_supporting) -
Ataxia-telangiectasia syndrome Pathogenic:5
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This sequence change creates a premature translational stop signal (p.Tyr264Ilefs*12) 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 (rs774609577, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 12673797, 12815592, 15928302, 16832357, 22213089, 24549055). ClinVar contains an entry for this variant (Variation ID: 141742). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: The ATM c.790delT (p.Tyr264Ilefs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.1027_1030delGAAA [p.Glu343fs). One in silico tool predicts a damaging outcome for this variant. The variant has been identified in numerous patients affected with ataxia telangiectasia and/or breast cancer and has not been observed in healthy individuals (e.g., Renwick_2006; Buzin_2003; Castera_2014). In addition, a functional study revealed that a patient carrying the variant of interest and a second truncating ATM variant (c.1563_1564delAG [p.Glu522fs]) had no detectable ATM expression or kinase activity (Verhagen_HM_2012), suggesting the variant is a functional null allele. This variant is absent in the large control database ExAC (0/122508 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:4
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The c.790delT pathogenic mutation, located in coding exon 6 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 790, causing a translational frameshift with a predicted alternate stop codon (p.Y264Ifs*12). This alteration has been reported in conjunction with a second pathogenic mutation in multiple individuals diagnosed with ataxia-telangiectasia (A-T) (Sandoval N et al. Hum Mol. Genet. 1999 Jan;8(1):69-79; Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50; Buzin C et al. Hum. Mutat. 2003 Feb;21(2):123-31; Heinrich T et al. Eur. J. Pediatr. 2006 Apr;165(4):250-7; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). This alteration has also been identified in individuals diagnosed with prostate cancer, breast cancer and colorectal cancer (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53; Decker B et al. J. Med. Genet., 2017 Nov;54:732-741; Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102; Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). 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. -
This variant deletes 1 nucleotide in exon 7 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 ataxia-telangiectasia (PMID: 9887333, 10817650, 12552559, 12815592, 15928302, 16411093, 21665257, 22213089, 25122203). This variant has also been reported in individuals affected with breast, ovarian, colorectal and prostate cancer (PMID: 16832357, 19781682, 20346647, 24549055, 27433846, 27616075, 28135145, 28779002). This variant has been identified in 2/251032 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. -
not provided Pathogenic:3
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; 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; Observed in individuals with personal and/or family history of ATM-related cancers (Renwick et al., 2006; Castera et al., 2014; Pritchard et al., 2016; Decker et al., 2017); This variant is associated with the following publications: (PMID: 16832357, 16411093, 29625052, 32853339, 26896183, 32818697, 35154108, 29922827, 35047863, 29478780, 9887333, 22213089, 12673797, 15928302, 12552559, 10817650, 20346647, 27616075, 27433846, 23566627, 28152038, 24549055, 28779002, 26689913, 31731261, 12815592) -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at