rs886039471
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PP3_Strong
The NM_000051.4(ATM):c.6814G>A(p.Glu2272Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,900 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2272Q?) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6814G>A | p.Glu2272Lys | missense_variant | 47/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6814G>A | p.Glu2272Lys | missense_variant | 47/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461750Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727186
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74328
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 12, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 19, 2018 | This variant is denoted ATM c.6814G>A at the cDNA level, p.Glu2272Lys (E2272K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual with childhood acute lymphoblastic leukemia (Gumy Pause 2003). ATM Glu2272Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Glu2272Lys is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Glu2272Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2016 | Variant summary: The ATM c.6814G>A (p.Glu2272Lys) variant involves the alteration of a conserved nucleotide. The variant is present in RAD-3 domain however it is unknown whether the domain is critical to protein function or it involves a critical residue. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 120880 control chromosomes. The variant was found as germline variant in one acute lymphoblastic leukemia sample and as somatic variant in one esophagus sample (Gumy Pause_2003, Lin_2014); however without strong evidence for causality. Because of the absence of sufficient clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 14, 2021 | - - |
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 12, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2272 of the ATM protein (p.Glu2272Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ataxia telangiectasia and with leukemia (PMID: 12673804, 31050087). ClinVar contains an entry for this variant (Variation ID: 265315). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 08, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 08, 2019 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 29, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2023 | The p.E2272K variant (also known as c.6814G>A), located in coding exon 46 of the ATM gene, results from a G to A substitution at nucleotide position 6814. The glutamic acid at codon 2272 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic ATM mutation in an individual with an atypical Ataxia Telangiectasia phenotype (Fiévet A et al. Hum Mutat, 2019 10;40:1713-1730). It was also identified in a pediatric patient with acute lymphoblastic leukemia and a woman with early-onset breast cancer (Gumy Pause et al. Hum. Mutat. 2003 May;21(5):554; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
ATM-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2023 | The ATM c.6814G>A variant is predicted to result in the amino acid substitution p.Glu2272Lys. This variant has been reported in an individual with acute lymphoblastic leukemia and an individual with breast cancer (Table 2, Gumy Pause et al. 2003. PubMed ID: 12673804; Supplement, Lerner-Ellis et al. 2021. PubMed ID: 32885271). It has also been reported along with a second ATM variant in an individual with atypical ataxia-telangiectasia (Patient AT26, Table S2, Fiévet et al. 2019. PubMed ID: 31050087). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108196791-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/265315/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Glu2272Lys variant was identified in 1 of 114 proband chromosomes (frequency: 0.009) from individuals or families with B-precursor ALL, and was not identified in 128 control chromosomes from healthy individuals (Pause 2003). The variant was identified in dbSNP (ID: rs886039471) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and in LOVD 3.0 (1x as pathogenic (2019)). The variant was identified in control databases in 1 of 30966 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 8728 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, South Asian, and Finnish, populations. The p.Glu2272 residue is conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Glu2272Lys 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at