rs778269655
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.8307G>A(p.Trp2769Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8307G>A | p.Trp2769Ter | stop_gained | 57/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8307G>A | p.Trp2769Ter | stop_gained | 57/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251376Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461744Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727186
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 23, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 12, 2022 | Variant summary: ATM c.8307G>A (p.Trp2769X) 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 8e-06 in 251376 control chromosomes (gnomAD). c.8307G>A has been reported in the literature in individuals affected with breast cancer or prostate cancer (Decker_2017, Nguyen-Dumont_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Trp2769*) 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 (rs778269655, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835). ClinVar contains an entry for this variant (Variation ID: 189104). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2023 | 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; Observed in individuals with a personal or family history of cancers consistent with pathogenic variants in this gene, including breast and prostate cancer (Thompson et al., 2016; Decker et al., 2017; Ghazani et al., 2017; Na et al., 2017; AlDubayan et al., 2018; Li et al., 2019; Karlsson et all., 2021); Observed in the compound heterozygous state in individuals with ataxia-telangiectasia (Gilad et al., 1996; Corts et al., 2003; Rbe et al., 2010); Published functional studies demonstrate a damaging effect: absence of protein expression, loss of kinase activity, and increased sensitivity to ionizing radiation (Corts et al., 2003); 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: 29752822, 35047863, 8845835, 26786923, 12883528, 29555025, 25133958, 20153123, 29478780, 28779002, 28125075, 27989354, 28716242, 25525159, 33436325, 9259193, 22649200, 29922827, 32338768, 33804961, 32853339, 26896183) - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 01, 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 | May 06, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 06, 2023 | This variant changes 1 nucleotide in exon 57 of the ATM gene, creating a 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 breast cancer (PMID: 26786923), pancreatic cancer (PMID: 33436325), and in the compound heterozygous state with a second ATM mutation in individuals affected with ataxia-telangiectasia (PMID: 8845835, 22649200). This variant has been identified in 2/251376 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2023 | The p.W2769* pathogenic mutation (also known as c.8307G>A), located in coding exon 56 of the ATM gene, results from a G to A substitution at nucleotide position 8307. This changes the amino acid from a tryptophan to a stop codon within coding exon 56. This mutation has been identified in several individuals with Ataxia-telangiectasia (AT) who also carried another mutation in the ATM gene (Gilad S, et al. Hum. Mol. Genet. 1996;5(4):433-9; Jackson TJ et al. Dev. Med. Child Neurol. 2016 07;58:690-7; Ambry internal data). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genetic. 2017 11;54:732-741) and was identified in 2/2000 Australian breast or ovarian cancer patients and 0/1997 controls undergoing multigene panel testing for hereditary cancer risk (Thompson ER et al, J. Clin. Oncol. 2016 May;34:1455-9). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at