rs730881303
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.237del(p.Lys79AsnfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A78A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
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.237del | p.Lys79AsnfsTer37 | frameshift_variant | 4/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.237del | p.Lys79AsnfsTer37 | frameshift_variant | 4/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250502Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135448
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461162Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726824
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2017 | Variant summary: The ATM c.237delA (p.Lys79Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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 (e.g. p.Tyr171X, p.Arg2993X, p.Lys2756X, etc.). This variant is absent in 114158 control chromosomes from ExAC. This variant has previously been reported in one A-T patient in compound heterozygous state with p.Tyr124Ter (Minto et al. 2017; a conference meeting abstract) and in one ovarian cancer patient (Susswein_2015). One clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 06, 2021 | PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Lys79Asnfs*37) 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 (rs730881303, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 181874). For these reasons, this variant has been classified as Pathogenic. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 08, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 07, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2021 | The c.237delA pathogenic mutation, located in coding exon 3 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 237, causing a translational frameshift with a predicted alternate stop codon (p.K79Nfs*37). This mutation was identified in trans with a second truncating allele in a child with AT (Susswein LR et al. Genet Med, 2016 08;18:823-32) and identified heterozygous an individual diagnosed with ovarian 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 1 nucleotide in exon 4 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 identified in 1/250502 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | Frameshift variant predicted to result in protein truncation or 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: 29922827, 26681312, 23807571, 25614872, 30639167) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at