rs587781894
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The NM_000051.4(ATM):c.9023G>A(p.Arg3008His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,000 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3008G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.9023G>A | p.Arg3008His | missense_variant | 63/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.9023G>A | p.Arg3008His | missense_variant | 63/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251410Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 21, 2023 | This missense variant replaces arginine with histidine at codon 3008 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Mouse models carrying this variant were immunodeficient and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared with wild type controls (PMID: 33239428). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 21665257, 30549301). This variant has also been reported in individuals with a personal and/or family history of breast cancer or colorectal cancer (PMID: 19404735, 29752822, 31118792). In addition, a different variant affecting the same amino acid position (p.Arg3008Cys) is considered to be disease-causing (ClinVar variation ID: 142187), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 2/246168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The p.R3008H variant (also known as c.9023G>A), located in coding exon 62 of the ATM gene, results from a G to A substitution at nucleotide position 9023. The arginine at codon 3008 is replaced by histidine, an amino acid with highly similar properties. In one study, this alteration was reported in conjunction with a nonsense ATM mutation in a child with ataxia-telangiectasia (A-T). In the same study, this alteration was detected in 1/122 breast cancer patients with a family history of both breast cancer and a hematological malignancy and was not seen in any of the 186 control patients (Paglia LL et al. Breast Cancer Res.Treat. 2010; 119:443-52). This variant has also been reported in conjunction with a frameshift ATM mutation in a Norwegian patient with A-T (Strand J et al. Front Immunol, 2020 Jul;11:1417). This variant was also reported in conjunction with a leaky splice site variant in ATM in a 45 year old patient and in three siblings with variant type A-T (Schon K et al. Ann. Neurol., 2019 02;85:170-180; Caputi C et al. Mov Disord Clin Pract, 2023 Jan;10:124-129). A functional study performed in p.R3008H expressing mice demonstrated the mice are viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared to Atm-/- controls; the mutant animals also displayed cell cycle checkpoint defects and reduced lymphocyte development (Milanovic M et al. Cancer Res, 2021 Jan;81:426-437). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 02, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | The c.9023G>A (p.Arg3008His) variant has an allele frequency of 0.00075%, (2/268,268 alleles) in the gnomAD v2.1.1 non-cancer dataset, since it has been found once in the Finnish subpopulation (1/25,106) and once in the European non-Finnish subpopulation (1/118,102 alleles) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. However, the in silico protein effect prediction for this missense variant is inconclusive. On the other side, it is located at the somatic mutational hotspot codon p.Arg3008 (PM1). Moreover, the pathogenic variant c.9022C>T p.(Arg3008Cys) is located in the same codon. This variant was detected in two ataxia-telangiectasia probands (PS4_Moderate; PMID: 30549301, 21665257). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PM1 + PS4_Moderate (PMID: 33280026). - |
Ataxia-telangiectasia syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3008 of the ATM protein (p.Arg3008His). This variant is present in population databases (rs587781894, gnomAD 0.004%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or personal or family history of breast, ovarian, and/or colon cancer (PMID: 2166257, 19404735, 21665257, 29752822, 31118792, 32754152). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 141634). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg3008 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9872980, 10817650, 12552566, 15101044, 18573109, 19431188). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 02, 2020 | - - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 06, 2024 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 32754152]. Functional studies indicate this variant impacts protein function [PMID: 33239428, 12552566, 18573109, 23585524]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Observed in a patient with ataxia telangiectasia who harbored an ATM truncating variant, but information regarding phase (variants in cis or trans) was not provided (PMID: 21665257); Observed in the heterozygous state in individuals with a personal or family history of breast, colorectal, and other cancers (PMID: 19404735, 31118792, 29752822, 33436325); Published functional studies demonstrate a damaging effect: reduced or normal ATM protein expression, deficient p21 induction, and reduced ATM kinase activity (PMID: 11756177, 33239428, 23585524); 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: 17968022, 12697903, 25742471, 12149228, 28152038, 27586204, 29752822, 30620386, 19404735, 22529920, 10397742, 11756177, 23585524, 21933854, 27714650, 23103869, 26536348, 25925381, 26205736, 29316426, 29922827, 29946849, 29866652, 27194209, 28652578, 30549301, 30855176, 31118792, 32754152, 33332384, 33436325, 32873698, 34771661, 33598286, 33280026, 35480123, 33239428, 34556870, 34151669, 35347810, 31263571, 33536256, Villaruz2022[Abstract], 23532176, 21665257, 35264596, 35886069) - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 11, 2022 | Variant summary: ATM c.9023G>A (p.Arg3008His) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251410 control chromosomes (gnomAD). c.9023G>A has been reported in the literature in individuals affected with Breast Cancer (Li_2018, Pagila_2010), Ataxia-Telangiectasia (Micol_2011, Schon_2019), colorectal cancer (Gong_2019), along with multiple somatic occurrences (Austen_2007, Camacho_2002, Chang_2015, Fang_2003, Gronbaek_2002, Ida_2019, Navrkalova_2013, Schaffner_1999). These data indicate that the variant is likely to be associated with disease. In addition, another missense change at this position, R3008C, has been highly reported to be associated with cancer and A-T. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic (n=7)/pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at