ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6543G>T (p.Glu2181Asp)

gnomAD frequency: 0.00056  dbSNP: rs138828590
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587205 SCV000149139 uncertain significance not provided 2021-12-06 criteria provided, single submitter clinical testing Observed in individuals with breast cancer (Bernstein 2010, Tung 2016, Adedokun 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30413523, 26976419, 26689913, 21787400, 25182519, 20305132, 23555315, 28652578, 32098697, 31871109, 23532176)
Ambry Genetics RCV000115230 SCV000214314 likely benign Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Invitae RCV000196735 SCV000254131 likely benign Ataxia-telangiectasia syndrome 2021-12-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115230 SCV000537555 likely benign Hereditary cancer-predisposing syndrome 2020-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212044 SCV000694327 benign not specified 2022-04-01 criteria provided, single submitter clinical testing Variant summary: ATM c.6543G>T (p.Glu2181Asp) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing the Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was found in 8/2559 African American women (allele frequency: 0.001563) older than 70 years of age, who had no history of cancer (FLOSSIES database). c.6543G>T has also been reported in the literature in individuals affected with Breast Cancer (e.g. Bernstein 2010, Haiman_2013, Tung 2016, Adedokun_2020, George_2021, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with a pathogenic variant ATM c.3049C>T (p.Gln1017X) has been seen multiple times in our lab, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, and two as likely benign. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Eurofins NTD LLC (GA) RCV000587205 SCV000703945 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Mendelics RCV000196735 SCV000838576 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212044 SCV002070968 uncertain significance not specified 2017-10-09 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225324 SCV002504755 uncertain significance Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115230 SCV002537947 likely benign Hereditary cancer-predisposing syndrome 2021-04-21 criteria provided, single submitter curation

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