rs778482902
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000051.4(ATM):c.7370A>C(p.Glu2457Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,092 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E2457E) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7370A>C | p.Glu2457Ala | missense_variant | 50/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7370A>C | p.Glu2457Ala | missense_variant | 50/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152250Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251274Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135806
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461842Hom.: 1 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727224
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74384
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2022 | This missense variant replaces glutamic acid with alanine at codon 2457 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 36200007). This variant has been identified in 11/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 22, 2022 | The p.E2457A variant (also known as c.7370A>C), located in coding exon 49 of the ATM gene, results from an A to C substitution at nucleotide position 7370. The glutamic acid at codon 2457 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 09, 2020 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.E2457A in ATM (NM_000051.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.E2457A variant has a GnomAD frequency of 0.00004378 % and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glutamic acid and alanine. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu2457Ala in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2018 | This variant is denoted ATM c.7370A>C at the cDNA level, p.Glu2457Ala (E2457A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Glu2457Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 evidence, it is unclear whether ATM Glu2457Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at