ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6543G>T (p.Glu2181Asp) (rs138828590)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587205 SCV000149139 uncertain significance not provided 2021-05-25 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)
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 uncertain significance Ataxia-telangiectasia syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 2181 of the ATM protein (p.Glu2181Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs138828590, ExAC 0.2%). This variant has been reported in individuals affected with breast cancer (PMID: 26976419, 20305132), and individuals affected with endometrial cancer and low grade glioma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127425). 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 disruptive, 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.
Color Health, Inc 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 likely benign not specified 2021-01-27 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, 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 Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant was also found in 8/2559 African American women (0.003126) older than 70 years who have never had cancer (FLOSSIES database). c.6543G>T has been reported in the literature in individuals affected with Breast Cancer (example, Bernstein 2010, Tung 2016, van Marcke_2018, Adedokun_2020) and in other types of cancer (example, Haiman_2013, TGCA cohort, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with hereditary or familial forms of Breast Cancer. Co-occurrences with other pathogenic variant(s) have been observed at our laboratory (ATM c.3049C>T, p.Gln1017X, phase unknown), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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

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