rs1057516980
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.2377_2378dup(p.Ser794ArgfsTer15) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K792K) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift, splice_region
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.2377_2378dup | p.Ser794ArgfsTer15 | frameshift_variant, splice_region_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2377_2378dup | p.Ser794ArgfsTer15 | frameshift_variant, splice_region_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2020 | 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 not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 371070). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser794Argfs*15) in the ATM gene. It is expected to result in an absent or disrupted protein product. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 16, 2016 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 17, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2022 | The c.2377_2378dupAA pathogenic mutation, located in coding exon 15 of the ATM gene, results from a duplication of AA at nucleotide position 2377, causing a translational frameshift with a predicted alternate stop codon (p.S794Rfs*15). 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