rs1450394308
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.7886_7890delTATTA(p.Ile2629SerfsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.7886_7890delTATTA | p.Ile2629SerfsTer25 | frameshift_variant | Exon 53 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.7886_7890delTATTA | p.Ile2629SerfsTer25 | frameshift_variant | Exon 53 of 63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250834 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460882Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726768 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:8Other:1
This sequence change creates a premature translational stop signal (p.Ile2629Serfs*25) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with ataxia-telangiectasia and breast cancer and/or ovarian cancer (PMID: 8845835, 9600235, 12815592, 21787400, 23322442, 23946315, 26436112). This variant is also known as 7883del5, 7884_7888del5, c.7878_7882delTTATA and c.7886_7890del. ClinVar contains an entry for this variant (Variation ID: 230200). For these reasons, this variant has been classified as Pathogenic. -
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. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia, and in association with cancer (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Variant summary: ATM c.7886_7890delTATTA (p.Ile2629SerfsX25) 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 250834 control chromosomes (gnomAD). This variant has been reported in several A-T patients/families across multiple countries in homozygous state as well as in compound heterozygous state with other pathogenic/likely pathogenic variants (Gilad_1996, Telatar_1996, Sasaki_1998, Stankovic_1998, Exley_2011, Mitui_2003, Jeddane_2013, Charlesworth_2013). Cosegregation of this variant with disease have also been reported from a family (Charlesworth_2013). It has also been found in a breast cancer patient (Hirotsu_2015), which is consistent with the fact that pathogenic variants in ATM gene are known to confer elevated risk of breast cancer in a heterozygous state. In a compound heterozygous patient that carried this variant and 3802delG, no ATM kinase activity and ATM protein expression was observed in lymphoblastoid cell line derived from the patient, strongly supporting its predicted outcome (Exley_2011). These data indicate that the variant is likely to be associated with disease. Eleven ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=1) and pathogenic (n=10). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
The c.7886_7890delTATTA pathogenic mutation, located in coding exon 52 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 7886 to 7890, causing a translational frameshift with a predicted alternate stop codon (p.I2629Sfs*25). This pathogenic mutation has been reported in a family with two cases of breast cancer under age 50 and one individual with ataxia-telangiectasia (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). This mutation has also been reported in a compound heterozygous state with another alteration in ATM [c.6154G>A (p.E2052K)] in an individual with cervical dopa-responsive dystonia (DRD) (Charlesworth G et al. Neurology. 2013 Sep;81:1148-51). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was also observed with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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 5 nucleotides in exon 53 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. This variant (also known as 7883del5, 7884_7888del5, or c.7878_7882delTTATA in the literature) has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8845835, 9600235, 12815592, 23322442, 23946315). This variant has also been reported in individuals affected with breast cancer (PMID: 21787400, 26436112, 30287823, 33471991) or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant has been identified in 1/250834 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. -
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Familial cancer of breast Pathogenic:3
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic for 'Ataxia-telangiectasia (OMIM: 208900)' and as risk allele for breast cancer with clinical assertions and evidence for the classification (ClinVar ID: VCV000230200 /PMID: 8845835). Therefore, this variant is classified as Risk allele according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:2
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 individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Goldgar 2011, Hirotsu 2015, Momozawa 2018, Kaneyasu 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.7883del5, c.7884_7888del5, c.7886_7889del5, and c.7878_7882del; This variant is associated with the following publications: (PMID: 8845835, 21459046, 21787400, 23946315, 9463314, 20346647, 9711876, 26436112, 9443866, 34489640, 29360550, 30287823, 32566746, 34262154, 9600235, 23322442, 12815592) -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
PM2_Supporting+PVS1+PM3 -
Gastric cancer Pathogenic:1
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Hereditary breast ovarian cancer syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at