rs758852420
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.5631_5635delinsA(p.Phe1877LeufsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
ATM
NM_000051.4 frameshift
NM_000051.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.26
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108304809-CTCGC-A is Pathogenic according to our data. Variant chr11-108304809-CTCGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5631_5635delinsA | p.Phe1877LeufsTer39 | frameshift_variant | 37/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5631_5635delinsA | p.Phe1877LeufsTer39 | frameshift_variant | 37/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2018 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Phe1877Leufs*39) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 15843990). ClinVar contains an entry for this variant (Variation ID: 233573). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2022 | The c.5631_5635delCTCGCinsA pathogenic mutation, located in coding exon 36 of the ATM gene, results from the deletion of 5 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.F1877Lfs*39). This alteration, described as c.5631_5635delCTCGC+5639_5640insA, has been reported in two individuals from a cohort of Iranian ataxia-telangiectasia patients (Babaei M et al, Hum. Genet. 2005 Jul; 117(2-3):101-6) as well as in three individuals from an Indian ataxia-telangiectasia patient cohort (Rawat A et al, Sci Rep. 2022 03;12(1):4036). 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 16, 2024 | This variant deletes 5 nucleotides and inserts 1 new nucleotide in exon 37 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 the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 15843990, 35729272). This variant has also been reported in individuals affected with triple negative breast cancer (DOI: 10.1101/2022.05.31.22275080). 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. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 25, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.5631_5635delinsA (p.Phe1877LeufsTer39) in ATM has been reported in heterozygous state in individuals affected with ataxiatelangiectasia (Babaei M et al.). The p.Phe1877LeufsTer39 variant is novel in the gnomAD Exomes database. It has been submitted to ClinVar as Pathogenic and Likely Pathogenic. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-offunction variants in ATM are known to be pathogenic (Huang Y et al.). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 23, 2019 | 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15843990) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at