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

gnomAD frequency: 0.00005  dbSNP: rs587782397

Total submissions: 12

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