11-108345797-C-CAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.8476_8477dup(p.Asn2826LysfsTer32) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q2825Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8476_8477dup | p.Asn2826LysfsTer32 | frameshift_variant | 58/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8476_8477dup | p.Asn2826LysfsTer32 | frameshift_variant | 58/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461502Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727052
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2023 | Variant summary: ATM c.8476_8477dupAA (p.Asn2826LysfsX32) 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 was absent in 251310 control chromosomes. c.8476_8477dupAA has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Stankovic_1998). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant has been observed in an individual affected with ataxia-telangiectasia (PMID: 9463314). This variant is also known as insAA at position 8478 in the literature. ClinVar contains an entry for this variant (Variation ID: 186852). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn2826Lysfs*32) in the ATM gene. It is expected to result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 29, 2024 | The c.8476_8477dupAA pathogenic mutation, located in coding exon 57 of the ATM gene, results from a duplication of AA at nucleotide position 8476, causing a translational frameshift with a predicted alternate stop codon (p.N2826Kfs*32). This alteration was reported in a cohort of individuals diagnosed with ataxia-telangiectasia (A-T) (Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62:334-45). Of note, this alteration is also known as 8478 ins AA in published literature. 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. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 02, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at