rs146069748
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000051.4(ATM):c.7531A>T(p.Ile2511Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,218 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I2511I) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7531A>T | p.Ile2511Phe | missense_variant | 51/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7531A>T | p.Ile2511Phe | missense_variant | 51/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251002Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135726
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461172Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726896
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74250
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2021 | The p.I2511F variant (also known as c.7531A>T), located in coding exon 50 of the ATM gene, results from an A to T substitution at nucleotide position 7531. The isoleucine at codon 2511 is replaced by phenylalanine, an amino acid with highly similar properties. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 28, 2023 | This missense variant replaces isoleucine with phenylalanine at codon 2511 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 1/251002 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. - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2511 of the ATM protein (p.Ile2511Phe). This variant is present in population databases (rs146069748, gnomAD 0.007%). 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: 142726). 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. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 06, 2015 | This variant is denoted ATM c.7531A>T at the cDNA level, p.Ile2511Phe (I2511F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATT>TTT). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. ATM Ile2511Phe was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Ile2511Phe occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013, UniProt). 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 Ile2511Phe is pathogenic or benign. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at