chr11-108325416-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.6679C>T(p.Arg2227Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,530 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 (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.6679C>T | p.Arg2227Cys | missense_variant | Exon 46 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152006Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461524Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727078
GnomAD4 genome 0.0000132 AC: 2AN: 152006Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74252
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:7Other:1
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This sequence change in ATM is predicted to replace arginine with cysteine at codon 2227, p.(Arg2227Cys). The arginine residue is highly conserved (93/95 vertebrates, UCSC), and is located in the FAT domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.005% (2/41,396 alleles) in the African/African American population. This variant has been detected in multiple individuals with a definitive diagnosis of ataxia-telangiectasia (A-T) in the homozygous state and compound heterozygous with a second pathogenic variant (PMID: 18634022, 28126470, 32548172). This variant has been reported heterozygous in multiple individuals with breast cancer (PMID: 30607632, 36119527). In vitro expression of the variant in an A-T (ATM null) cell line demonstrated failure-to-rescue target phosphorylation and intermediate radiosensitivity. Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.854). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Moderate, PP3. -
The variant is not observed in the gnomAD v2.1.1 dataset. While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181981). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16380133 , 18504682 , 19691550 , 22213089 , 23264026 , 23640770). A different missense change at the same codon (p.Arg2227Leu) has been reported to be associated with ATM-related disorder (PMID: 21665257). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2227 of the ATM protein (p.Arg2227Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia (A-T) (PMID: 12552559, 15843990, 16380133, 18504682, 19691550, 22213089, 23264026, 23640770). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181981). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 18634022, 23640770). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:6
Identified in the single heterozygous state in individuals with breast cancer (Sun 2017); Published functional studies in patient cells demonstrate reduced ATM protein expression, reduced kinase activity, and increased radiosensitivity (Becker-Catania 2000, Mitui 2009, Meissner 2013, Fievet 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22213089, 22529920, 26681312, 15101044, 23264026, 25572163, 21665257, 18634022, 27479817, 19691550, 25480502, 23807571, 16380133, 23640770, 10873394, 9887333, 22927201, 26491069, 12552559, 10817650, 15843990, 28724667, 18504682, 29335925, 30322717, 31159747, 30607632, 31050087, 31921190, 23532176, 33436325, 32338768) -
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.6679C>T, in exon 46 that results in an amino acid change, p.Arg2227Cys. This sequence change has not been described in population databases such as ExAC and gnomAD (db SNP rs564652222). The p.Arg2227Cys change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2227Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in the compound heterozygous state in individuals with ataxia telangiectasia and in the heterozygous state in individuals with breast cancer (PMID: 12552559, 15843990, 16380133, 18504682, 19691550, 22213089, 23264026, 23640770, 28724467, 29335925, 30607632). Experimental studies have demonstrated that this sequence change impacts the function of the ATM protein (PMID: 18634022, 23640770). Collectively, these evidences indicate that this sequence change is pathogenic. -
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The ATM p.Arg2227Cys variant was identified in 13 of 1078 proband chromosomes (frequency: 0.01206) from individuals or families with ataxia-telangiectasia (A-T) (Babaei_2005, Becker_Catania_2000, Buzin_2003, Chessa_2009, Gutierrez_Enriquez_2004, Li_2000, Meissner_2013, Sandoval_1999, Verhagen_2011). The variant was also identified in dbSNP (ID: rs564652222) as “With Pathogenic allele”, ClinVar (as pathogenic by GeneDx, Ambry Genetics, Invitae, Color Genomics, and Gene Reviews), Clinvitae (3x), and Cosmic (in haemotopoietic and lymphoid cancer and in salivary gland cancer). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). Several functional studies of ATM protein levels in A-T patients showed the p.Arg2227Cys variant exhibited reduced ATM expression (Becker_Catania_2000, Mitui_2009). In one study, the variant was shown to co-segregate with three affected siblings (Meissner_2013). Computational studies have also reported the variant as deleterious (Doss_2012). A newborn screening study of infants with severe combined immunodeficiency has also identified the variant in an affected infant (Mallott_2013). The p.Arg2227 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:4
The p.R2227C pathogenic mutation (also known as c.6679C>T), located in coding exon 45 of the ATM gene, results from a C to T substitution at nucleotide position 6679. The arginine at codon 2227 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in a compound heterozygous state with an additional ATM mutation in multiple individuals with Ataxia-telangiectasia (Babaei M et al. Hum. Genet. 2005 Jul;117:101-6; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Becker-Catania SG et al. Mol. Genet. Metab., 2000 Jun;70:122-33). This alteration has also been reported in three siblings diagnosed with isolated generalized dystonia who were found to be compound heterozygotes for p.R2227C and p.I191N in the ATM gene. This family also included two siblings diagnosed with early onset breast cancer and increased levels of alpha-fetoprotein in blood. Further studies indicated that the p.R2227C alteration led to protein levels of only 20-35% of wild-type and nearly absent ATM kinase activity (Meissner WG et al. Mov. Disord. 2013 Nov;28:1897-9). Another group evaluated the effect of the p.R2227C variant on the cellular phenotype of a transfected and transduced host A-T cell line (AT7LA) and found only trace amounts of ATM protein were detectable. The authors conclude that p.R2227C is a disease-causing mutation, but also note that it most likely represents a “mild” mutation, accounting for the associated mild clinical phenotype (Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). 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, this alteration is classified as a pathogenic mutation. -
This is a single base substitution replacing the amino acid Arginine with Cysteine in the position 2227 of the ATM protein. This particular Arginine is highily conserved and located in a known functional domain, while the physiochemical difference between Arginine and Cysteine is high (Grantham Score 180). This finding is not present in population databases. The mutation database ClinVar contains an entry for this variant (Variation ID: 181981). Algorithms developed to estimate the effect of point mutations on the function and structure of the protein estimate that this change may affect the function or structure of the protein, which is confirmed by recent functional studies of the mutant protein where they showed decreased expression of ATM and reduced ATM kinase activity (PMID: 23640770, PMID: 18634022 ). -
This missense variant replaces arginine with cysteine at codon 2227 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). Functional studies have shown that this variant results in reduced ATM protein expression and kinase activity in cell-based assays (PMID: 18634022). This variant has been reported in the compound heterozygous state with an additional ATM pathogenic variant in multiple individuals and families affected with ataxia telangiectasia (PMID: 12552559, 15843990, 16380133, 18504682, 19691550, 22213089, 23264026, 23640770). Cells derived from some of these individuals have shown reduced ATM protein levels and kinase activity and increased radiation sensitivity (PMID: 23640770). This variant has also been reported in individuals affected with breast cancer (PMID: 28724467, 29335925, 30607632, 33471991; Color Health, Inc internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
The c.6679C>T (p.Arg2227Cys) variant is variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and although a cryptic acceptor site is activated according to SSF and MaxEnt (not NNSplice or GeneSplicer), it does not exceed the natural one. However, it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). The variant has been detected in at least four ataxia telangiectasia probands (PS4; PMID: 9887333, 10873394, 12552559, 10817650). Lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no detectable ATM p.Ser1981 autophosphorylation, almost absent transphosphorylation activity on SMC1 p.Ser957/p.Ser966 and intermediate or severe radiosensitivity (PS3_Moderate; PMID: 10873394, 18634022). Moreover, there are 3 atypical ataxia-telangiectasia affected siblings in 1 family (compound heterozygotes) cosegregating with the variant (PP1; PMID: 23640770). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PS4 + PP3 + PS3_Moderate + PP1 (PMID: 33280026). -
Familial cancer of breast Pathogenic:3
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This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16380133, 21665257]. -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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Malignant tumor of breast Pathogenic:1
Variant summary: ATM c.6679C>T (p.Arg2227Cys) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251146 control chromosomes (gnomAD). c.6679C>T has been reported in the literature in multiple individuals in compound heterozygous state affected with ataxia-telangiectasia and Hodgkin disease (Gutierrez-Enriquez_2004, Mitui_2009, Meissner_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant effect results in reducing ATM protein level, ATM kinase activity and shown as severe in radiation sensitivity (Mitui_2009, Meissner_2013). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at