rs587782397
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000051.4(ATM):c.2476A>C(p.Ile826Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I826M) 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2476A>C | p.Ile826Leu | missense_variant | 17/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2476A>C | p.Ile826Leu | missense_variant | 17/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251320Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135824
GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727170
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 826 of the ATM protein (p.Ile826Leu). This variant is present in population databases (rs587782397, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer and/or chronic lymphocytic leukemia (PMID: 19404735, 20305132, 21993670, 28652578). ClinVar contains an entry for this variant (Variation ID: 142345). 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 tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 16, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, renal cancer, or leukemia, but also in unaffected controls (Paglia et al., 2010; Guarini et al., 2012; Lu et al., 2015; Navrkalova et al., 2016; Decker et al., 2017; Tiao et al., 2017); This variant is associated with the following publications: (PMID: 19404735, 21993670, 27479817, 26689913, 28779002, 28652578, 20305132) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 03, 2020 | - - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2022 | The p.I826L variant (also known as c.2476A>C), located in coding exon 16 of the ATM gene, results from an A to C substitution at nucleotide position 2476. The isoleucine at codon 826 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in 1/122 breast cancer patients with a family history of breast cancer and a hematologic malignancy and was not identified in 186 control samples (Paglia L et al. Breast Cancer Res Treat. 2010 Jan;119:443-52). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 06, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 13, 2021 | Variant summary: ATM c.2476A>C (p.Ile826Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251692 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.2476A>C, has been reported in the literature in individuals affected with Breast Cancer (Bernstein_2010) and CLL (Guarini_2012, LaPaglia_2009, Tiao_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at