11-108235772-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000051.4(ATM):āc.434T>Gā(p.Leu145Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,438 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).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.434T>G | p.Leu145Arg | missense_variant | Exon 5 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461438Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727038
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.L145R variant (also known as c.434T>G), located in coding exon 4 of the ATM gene, results from a T to G substitution at nucleotide position 434. The leucine at codon 145 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with ataxia telangiectasia (Podralska MJ et al. Mol Genet Genomic Med, 2014 Nov;2:504-11; Czarny J et al. Int J Mol Sci, 2023 Jan;24:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): not in gnomAD v3.1.2 (non cancer), PM3 (strong pathogenic): Found compound heterozygous in multiple Cases with AT PMID: 36674612 (Czarny et al.,2023) PMID: 25614872 (Podralska MJ et al., 2014), PP3 (supporting pathogenic): CADD:27.8 REVEL: 0.936 BayesDEL:0.334485 -
Ataxia-telangiectasia syndrome Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 145 of the ATM protein (p.Leu145Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 25614872). ClinVar contains an entry for this variant (Variation ID: 453518). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at