rs786202695
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):βc.2720_2723delβ(p.Cys907Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L906L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.2720_2723del | p.Cys907Ter | frameshift_variant | 18/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2720_2723del | p.Cys907Ter | frameshift_variant | 18/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461780Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727198
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 17, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Cys907*) 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 chronic lymphocytic leukemia and ataxia-telangiectasia (PMID: 10817650, 21933854). ClinVar contains an entry for this variant (Variation ID: 186103). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 02, 2021 | This variant deletes 4 nucleotides in exon 18 of the ATM gene, creating a frameshift and 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 ataxia telangiectasia (PMID: 10817650, 19691550). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 14, 2022 | The c.2720_2723delGTGT pathogenic mutation, located in coding exon 17 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 2720 to 2723, causing a translational frameshift with a predicted alternate stop codon (p.C907*). This alteration was previously reported in a cohort of 37 patients with a clinical diagnosis of ataxia telangiectasia (A-T) (Li A, Am. J. Med. Genet. 2000 May; 92(3):170-7). It has also been described in two unrelated Italian families with A-T that share the same haplotype, suggesting that it is a rare founder mutation (Chessa L, et al. Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9). Of note, this alteration has also been designated as 2720_2723delTGTG in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 18, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at