ClinVar Miner

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

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Total submissions: 6
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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 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131419 SCV000910809 likely benign Hereditary cancer-predisposing syndrome 2016-08-06 criteria provided, single submitter clinical testing
Counsyl RCV000168043 SCV000799988 uncertain significance Ataxia-telangiectasia syndrome 2018-05-16 criteria provided, single submitter clinical testing
GeneDx RCV000484154 SCV000566330 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.2476A>C at the cDNA level, p.Ile826Leu (I826L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATC>CTC). This variant was observed in the germline of individuals with breast cancer, one of which had a family history of leukemia or lymphoma, in a normal tissue sample from an individual with clear cell renal cancer, as well as in individuals with CLL, although it was not determined in some cases if the variant was of germline or somatic origin (Paglia 2010, Guarini 2012, Lu 2015, Navrkalova 2016, Decker 2017, Tiao 2017). This variant was also present in unaffected controls (Tiao 2017). ATM Ile826Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Ile826Leu is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ile826Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779790 SCV000916592 uncertain significance not specified 2018-08-27 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 4.3e-05 in 277444 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.3e-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 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000168043 SCV000218696 uncertain significance Ataxia-telangiectasia syndrome 2018-12-20 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, 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.

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