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 2018-11-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.6543G>T at the cDNA level, p.Glu2181Asp (E2181D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAT). This variant has been observed in individuals with breast cancer (Bernstein 2010, Tung 2016), and was also identified in normal tissue samples from individuals with endometrial cancer and low-grade glioma (Lu 2015). ATM Glu2181Asp was observed at an allele frequency of 0.19% (47/24,036) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Glu2181Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 RCV000115230 SCV000537555 likely benign Hereditary cancer-predisposing syndrome 2020-01-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212044 SCV000694327 likely benign not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: ATM c.6543G>T (p.Glu2181Asp) results in the alteration of a conserved nucleotide leading to 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 observed variant frequency within African control individuals in the gnomAD database (0.002) 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 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). The variant, c.6543G>T, has been reported in the literature in individuals affected with Breast Cancer (Bernstein 2010, Tung 2016). However, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with another pathogenic variant have been reported in two internal samples (ATM c.3049C>T (p.Gln1017X)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four laboratories classified the variant as VUS and one classified it as Likely benign. 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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