chr11-108281103-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.3511C>T(p.Gln1171*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3511C>T | p.Gln1171* | stop_gained | Exon 24 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
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This sequence change creates a premature translational stop signal (p.Gln1171*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 10873394, 22071889, 28724667). ClinVar contains an entry for this variant (Variation ID: 231278). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 24 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant reduced ATM protein expression, increased alpha-fetoprotein, and resulted in radiosensitivity (PMID: 10873394, 22071889). This variant has been reported in the compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 10873394, 22071889). This variant has also been reported in individuals affected with breast cancer (PMID: 28724667, 30607632, 33471991) and high-grade serous ovarian cancer (PMID: 36000185). 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. -
The p.Q1171* pathogenic mutation (also known as c.3511C>T), located in coding exon 23 of the ATM gene, results from a C to T substitution at nucleotide position 3511. This changes the amino acid from a glutamine to a stop codon within coding exon 23. This mutation was observed in a cohort of 8085 unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Jul;doi: 10.1158/1078-0432.CCR-16-3227. [Epub ahead of print]). It was also reported in conjunction with another ATM alteration in an individual with ataxia telangiectasia, resulting in decreased expression of ATM protein and increased radiosensitivity measured by a cell colony survival assay (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun; 70(2):122-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:2
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at