rs786203421
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):βc.7000_7003delβ(p.Tyr2334GlnfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L2332L) 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.7000_7003del | p.Tyr2334GlnfsTer4 | frameshift_variant | 48/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7000_7003del | p.Tyr2334GlnfsTer4 | frameshift_variant | 48/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251036Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135676
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461636Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727122
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 14, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 15, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Tyr2334Glnfs*4) 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 (rs763554569, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 27433846). ClinVar contains an entry for this variant (Variation ID: 187035). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 4 nucleotides in exon 48 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 1/251036 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 | curation | Sema4, Sema4 | Oct 19, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2023 | The c.7000_7003delTACA pathogenic mutation, located in coding exon 47 of the ATM gene, results from a deletion of 4 nucleotides at positions 7000 to 7003, causing a translational frameshift with a predicted alternate stop codon (p.Y2334Qfs*4). This alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53). This alteration was also reported in a woman with breast cancer, melanoma, and a family history of breast cancer (Torrezan GT et al. Front Genet, 2018 May;9:161). 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. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 11, 2021 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2022 | 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); Observed in individuals with a personal and/or family history of melanoma, prostate cancer and/or breast cancer (Lu 2015, Pritchard 2016, Huang 2018, Torrezan 2018, Matejcic 2020, Palmer 2020); This variant is associated with the following publications: (PMID: 26689913, 27433846, 29625052, 32832836, 27535533, 29868112, 32427313, 31658756, 34153142) - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 30, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at