rs786204657
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.5188C>T(p.Arg1730Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,228 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1730R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.5188C>T | p.Arg1730Ter | stop_gained | 35/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5188C>T | p.Arg1730Ter | stop_gained | 35/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251138Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135718
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461270Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726938
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74206
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg1730*) 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 (rs764389018, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10425038, 12815592, 21792198, 22213089). ClinVar contains an entry for this variant (Variation ID: 189054). 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 11, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 22, 2021 | Variant summary: ATM c.5188C>T (p.Arg1730X) 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 251138 control chromosomes (gnomAD). c.5188C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia in both the homozygous and compound heterozygous state (example, Reiman_2011, Verhagen_2012, Driessen_2013 and Carranza_2017). These data indicate that the variant is associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 04, 2020 | This variant changes 1 nucleotide in exon 35 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 the homozygous and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 10425038, 12815592, 21665257, 21792198, 22213089). This variant has also been identified in 2/251138 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 | Aug 29, 2022 | The p.R1730* pathogenic mutation (also known as c.5188C>T), located in coding exon 34 of the ATM gene, results from a C to T substitution at nucleotide position 5188. This changes the amino acid from an arginine to a stop codon within coding exon 34. This mutation has been reported in individuals and families with ataxia telangiectasia (A-T), including in homozygous individuals with no ATM protein expression (Castellví-Bel S et al, Hum. Mutat. 1999 ; 14(2):156-62; Mitui M et al, Hum. Mutat. 2003 Jul; 22(1):43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19(1):161-174; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). 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
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 25, 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 | Feb 29, 2024 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2018 | This variant is denoted ATM c.5188C>T at the cDNA level and p.Arg1730Ter (R1730X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous or compound heterozygous state in several individuals with Ataxia-telangiectasia (Mitui 2003, Mitui 2005, Carranza 2017, van Os 2017) and is considered pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at