rs587779851
Variant summary
Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.5791delGinsCCT(p.Ala1931ProfsTer7) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1931V) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift, missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 22 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.5791delGinsCCT | p.Ala1931ProfsTer7 | frameshift_variant, missense_variant | Exon 39 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Ala1931Profs*7) 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, melanoma and pancreatic cancer (PMID: 10425038, 26681312). ClinVar contains an entry for this variant (Variation ID: 127411). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: ATM c.5791delinsCCT (p.Ala1931ProfsX7) 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 251034 control chromosomes (gnomAD). c.5791delinsCCT has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Castellvi-Bev_1999, Cavaciuti_2005, Micol_2011). 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. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was 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. -
not provided Pathogenic:2
The ATM c.5791delinsCCT (p.Ala1931Profs*7) variant alters the translational reading frame of the ATM mRNA and causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals with of ataxia-telangiectasia (PMID: 10425038 (1999), 21665257 (2011)). This variant has also been identified in an individual with melanoma and pancreatic cancer (PMID: 26681312 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Frameshift variant predicted to result in protein truncation and 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; This variant is associated with the following publications: (PMID: 10425038, 15390180, 26681312, 23807571, 25614872, 27304073, 25122203, 29101607, 21665257) -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
- -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.5791delGinsCCT pathogenic mutation, located in coding exon 38 of the ATM gene, results from the deletion of one nucleotide (G) and the insertion of three nucleotides (CCT), causing a translational frameshift with a predicted alternate stop codon (p.A1931Pfs*7). This mutation was reported in one individual of Philippine ancestry with ataxia-telangiectasia (Castellví-Bel S et al. Hum. Mutat. 1999; 14:156-62) and in an individual with a clinical history of melanoma and pancreatic cancer (Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). 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 is located in the ATM protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at