chr11-108315863-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.6047A>G(p.Asp2016Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D2016V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6047A>G | p.Asp2016Gly | missense_variant | 41/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6047A>G | p.Asp2016Gly | missense_variant | 41/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Jul 05, 2016 | This heterozygous variant in the ATM gene (autosomal recessive transmission) was identified in a male patient with ataxia telangiectasia, who also harbours another variant in the ATM gene (compound heterozygosity) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2016 of the ATM protein (p.Asp2016Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia telangiectasia and breast cancer (PMID: 9887333, 18634022, 21965147, 28120234, 31741144, 32658311). ClinVar contains an entry for this variant (Variation ID: 140823). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 18634022). For these reasons, this variant has been classified as Pathogenic. - |
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 26, 2024 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18634022, 21965147]. Functional studies indicate this variant impacts protein function [PMID: 18634022]. - |
Likely pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Abnormal central motor function Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2014 | The p.D2016G variant (also known as c.6047A>G), located in coding exon 40 of the ATM gene, results from an A to G substitution at nucleotide position 6047. The aspartic acid at codon 2016 is replaced by glycine, an amino acid with similar properties.This variant has been identified in the homozygous state in ataxia telangiectasia (A-T) patients of German and Iranian descent (Sandoval N et al. Hum Mol Genet. 1999;8(1):69-79; Babaei M et al. Hum Genet. 2005;117(2-3):101-6), and in combination with an ATM truncating mutation in a Turkish A-T patient (Demuth I et al. Neurogenetics. 2011;12(4):273-82). Two separate functional studies have shown that the p.D2016G variant produces only trace amounts of ATM protein, that the variant protein has no detectable kinase activity, and that cell lines containing this variant have increased radiosensitivity (Sandoval N et al. Hum Mol Genet. 1999;8(1):69-79; Mitui M et al. Hum Mutat. 2009;30(1):12-21.This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.05% (greater than 1800 alleles tested) in our clinical cohort (includes this individual).This amino acid position is highly conserved in available vertebrate species. 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. - |
Breast carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | - | Pathology: Invasive breast carcinoma with multifocal papillary growth pattern - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at