ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2476A>C (p.Ile826Leu) (rs587782397)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131419 SCV000186399 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-09 criteria provided, single submitter clinical testing 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.
Invitae RCV000168043 SCV000218696 uncertain significance Ataxia-telangiectasia syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 826 of the ATM protein (p.Ile826Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs587782397, ExAC 0.009%). This variant has been reported in the literature in individuals affected with breast cancer and chronic lymphocytic leukemia, as well as normal population control individuals (PMID: 19404735, 20305132, 21993670, 28652578). ClinVar contains an entry for this variant (Variation ID: 142345) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000484154 SCV000566330 uncertain significance not provided 2021-04-07 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 in published literature (Paglia 2010, Guarini 2012, Lu 2015, Navrkalova 2016, Decker 2017, Tiao 2017); This variant is associated with the following publications: (PMID: 19404735, 21993670, 27479817, 26689913, 28779002, 28652578, 20305132)
Counsyl RCV000168043 SCV000799988 uncertain significance Ataxia-telangiectasia syndrome 2018-05-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131419 SCV000910809 likely benign Hereditary cancer-predisposing syndrome 2016-08-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779790 SCV000916592 uncertain significance not specified 2021-08-13 criteria provided, single submitter clinical testing 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.
Athena Diagnostics Inc RCV000484154 SCV001143100 uncertain significance not provided 2020-12-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV000168043 SCV001462072 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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