ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2476A>C (p.Ile826Leu)

gnomAD frequency: 0.00005  dbSNP: rs587782397
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131419 SCV000186399 likely benign Hereditary cancer-predisposing syndrome 2024-06-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000168043 SCV000218696 uncertain significance Ataxia-telangiectasia syndrome 2024-01-29 criteria provided, single submitter clinical testing 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.
GeneDx RCV000484154 SCV000566330 uncertain significance not provided 2023-08-04 criteria provided, single submitter clinical testing 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)
Counsyl RCV000168043 SCV000799988 uncertain significance Ataxia-telangiectasia syndrome 2018-05-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health 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 RCV000484154 SCV001143100 uncertain significance not provided 2020-12-03 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000484154 SCV002010840 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV001762310 SCV002580576 uncertain significance Familial cancer of breast 2021-12-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV001762310 SCV004203705 uncertain significance Familial cancer of breast 2024-03-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001762310 SCV005084609 likely benign Familial cancer of breast 2024-05-09 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc. RCV000168043 SCV001462072 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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