rs587779837
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000051.4(ATM):c.4087A>G(p.Thr1363Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1363S) has been classified as Uncertain significance.
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4087A>G | p.Thr1363Ala | missense_variant | Exon 27 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248650Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134612
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461078Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726888
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
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The p.T1363A variant (also known as c.4087A>G), located in coding exon 26 of the ATM gene, results from an A to G substitution at nucleotide position 4087. The threonine at codon 1363 is replaced by alanine, an amino acid with similar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). This amino acid position is 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:1
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1363 of the ATM protein (p.Thr1363Ala). This variant is present in population databases (rs587779837, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127381). 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 not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. -
ATM-related cancer predisposition Uncertain:1
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not provided Uncertain:1
This variant is denoted ATM c.4087A>G at the cDNA level, p.Thr1363Ala (T1363A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr1363Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a neutral polar amino acid is replaced with a neutral non-polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider ATM Thr1363Ala to be a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at