rs748192003
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000051.4(ATM):c.8672G>A(p.Gly2891Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,599,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000051.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8672G>A | p.Gly2891Asp | missense_variant, splice_region_variant | 60/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8672G>A | p.Gly2891Asp | missense_variant, splice_region_variant | 60/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152048Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000484 AC: 7AN: 1447434Hom.: 0 Cov.: 30 AF XY: 0.00000971 AC XY: 7AN XY: 721034
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74246
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2024 | Published functional studies demonstrated intermediate cell survival and chromosomal damage in response to radiation, and reduced, but not absent, kinase activity (PMID: 22146522); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25625042, 19781682, 21787400, 27479817, 29872864, 28779002, 20346647, 23091097, 25480502, 21933854, 21792198, 25040471, 24825865, 29449575, 31101757, 30549301, 33309985, 32748564, 34600502, 16832357, 34326862, 23532176, 31056428, 32068069, 22146522, 33471991, 29667044) - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2022 | Variant summary: ATM c.8672G>A (p.Gly2891Asp) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 252470 control chromosomes (gnomAD and publication data). c.8672G>A has been reported in the literature in individuals affected with Breast Cancer, Pancreatic Cancer, Colorectal Cancer or Ataxia-Telangiectasia (Renwick_2006, Tavtigian_2009, Reiman_2011, Byrd_2012, Ohmoto_2018, Kwong_2020, Fujita_2020, Lipponen_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and it showed this variant was expressed at a similar protein level to the WT protein and has residual ATM kinase activity (Byrd_2012). Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | research | Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu | Jul 06, 2021 | The variant was found in a patient with recessively inherited ataxia and in compound with a novel frameshift mutation in the ATM gene. Previous studies have shown that this mutation have functional concequences. In addition, mutation affects a conserved position in the protein. However, the variant was classified as VUS because the information of the variant is not sufficient to confirm the pathogenicity of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 20, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2891 of the ATM protein (p.Gly2891Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or mild ataxia telangiectasia (PMID: 16832357, 19781682, 22146522). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This missense change has been observed to co-occur in individuals with a different variant in ATM that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 216235). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 22146522). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 29, 2021 | This missense variant replaces glycine with aspartic acid at codon 2891 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in individuals affected with breast cancer (PMID: 16832357, 19781682, 22146522, 28779002). One individual affected with breast cancer had a pathogenic ATM variant in trans, was sensitive to radiation, but did not exhibit classic ataxia telangiectasia symptoms (PMID: 22146522). A cell line derived from this individual showed reduced protein stability, reduced kinase activity, and reduced foci formation after DNA damage (PMID: 22146522). However, protein expression and function was higher compared to cell lines derived from individuals with classic ataxia telangiectasia (PMID: 22146522). In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has also been reported in an individual affected with chronic lymphocytic leukemia (PMID: 21933854) and an atomic bomb survivor affected with myelodysplastic syndrome (PMID: 31101757). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2024 | The p.G2891D variant (also known as c.8672G>A), located in coding exon 59 of the ATM gene, results from a G to A substitution at nucleotide position 8672. This variant impacts the first base pair of coding exon 59. The glycine at codon 2891 is replaced by aspartic acid, an amino acid with similar properties. This alteration was reported in conjunction with c.1A>G in a woman with mild ataxia telangiectasia diagnosed at age 44, following an adverse reaction to radiation therapy for breast cancer treatment. Although she was normally ambulant with no ataxia and minimal other neurologic features, her T lymphocytes and skin fibroblasts were unusually radiosensitive. Functional testing revealed that her lymphoblastoid cell lines had reduced ATM expression and reduced ATM kinase activity compared to wildtype, but expression and kinase activity were higher than with a classic AT (Byrd PJ et al. Br. J. Cancer. 2012 Jan;106(2):262-8). This alteration was identified in a Finnish individual with ataxia. This individual was also found to have ATM c.1813del however phase was not determined (Lipponen J et al. BMC Neurol, 2021 Oct;21:382). This alteration has also been detected in multiple cohorts of individuals diagnosed with breast cancer (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46; Decker B et al. J. Med. Genet. 2017 11;54:732-741; Kwong A et al. J Mol Diagn, 2020 Apr;22:544-554). This variant has been identified in 1/12503 unselected Japanese colorectal cancer patients and in 0/23705 controls (Fujita M et al. Clin Gastroenterol Hepatol. 2020 Dec 11;S1542-3565(20)31664-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at