rs786203697
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000051.4(ATM):c.7157C>A(p.Ala2386Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2386P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7157C>A | p.Ala2386Glu | missense_variant | 49/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7157C>A | p.Ala2386Glu | missense_variant | 49/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251314Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135822
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2386 of the ATM protein (p.Ala2386Glu). This variant is present in population databases (rs786203697, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 31050087, 34759960). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 187391). 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: 31050087, 34759960). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2016 | This variant is denoted ATM c.7157C>A at the cDNA level, p.Ala2386Glu (A2386E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala2386Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ala2386Glu occurs at a position that is conserved across species and is located in the FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Ala2386Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2023 | The p.A2386E variant (also known as c.7157C>A), located in coding exon 48 of the ATM gene, results from a C to A substitution at nucleotide position 7157. The alanine at codon 2386 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was seen as homozygous in two Lebanese siblings with features of ataxia telangiectasia (A-T) and determined to have an “atypical” phenotype. In vitro studies using patient-derived cell lines showed reduced, but not absent, protein levels, reduced response to heat treatment suggesting protein instability, and levels of p53-MCL similar to what is observed for A-T heterozygous carriers (Biagiotti S et al. Front Genet, 2021 Oct;12:759467). This alteration was detected in a cohort of 36 patients with A-T in another patient with “atypical” phenotype. ATM protein levels were 40% of wild-type, and kinase activity was considered "intermediary" (Fiévet A et al. Hum Mutat, 2019 Oct;40:1713-1730). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at