11-108365440-C-T
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM3_Strong
This summary comes from the ClinGen Evidence Repository: The c.9103C>T variant in ATM is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 3035 (p.Leu3035Phe). This variant has been detected in at least two unrelated individuals with Ataxia-Telangiectasia (PMIDs: 16941484, 30549301). This variant is absent in gnomAD v4.1.0. The computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_ Strong, PM2_Supporting, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10579342/MONDO:0700270/020
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.9103C>T | p.Leu3035Phe | missense_variant | Exon 63 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
The homozygous p.Leu3035Phe variant in ATM was identified by our study in one indivisual with Ataxia-Telangiectasia. This variant has been reported as a VUS in ClinVar by Ambry Genetics (ClinVar ID: 232110). This variant has been reported in the literature in the compound heterozygous state alongside the pathogenic variant p.Tyr111Ter (Cavaliere et al. 2006; PMID: 16941484). This variant was absent from large population studies. This variant has been reported in the literature in the compound heterozygous state alongside the pathogenic variant p.Tyr111Ter (Cavaliere et al. 2006; PMID: 16941484). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Leu3035Phe variant is uncertain. -
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 3035 of the ATM protein (p.Leu3035Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive ataxia-telangiectasia (PMID: 16941484, 26896183, 30549301). ClinVar contains an entry for this variant (Variation ID: 232110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt 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. -
ATM-related cancer predisposition Pathogenic:1
The c.9103C>T variant in ATM is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 3035 (p.Leu3035Phe). This variant has been detected in at least two unrelated individuals with Ataxia-Telangiectasia (PMIDs: 16941484, 30549301). This variant is absent in gnomAD v4.1.0. The computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_ Strong, PM2_Supporting, PP3) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.L3035F variant (also known as c.9103C>T), located in coding exon 62 of the ATM gene, results from a C to T substitution at nucleotide position 9103. The leucine at codon 3035 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration is located in the highly conserved and functionally critical FATC domain of the ATM protein (Lee JH and Paull TT, Oncogene 2007 Dec; 26(56):7741-8). In one study, this alteration was identified in a patient with ataxia telangiectasia along with a second mutation, although phase could not be confirmed (Cavalieri S et al., Hum. Mutat. 2006 Oct; 27(10):1061). 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. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 66000 alleles tested) in our clinical cohort. 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 p.L3035F remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at