ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7775C>G (p.Ser2592Cys) (rs755009196)

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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 RCV000166355 SCV000217143 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing The p.S2592C variant (also known as c.7775C>G), located in coding exon 51 of the ATM gene, results from a C to G substitution at nucleotide position 7775. The serine at codon 2592 is replaced by cysteine, an amino acid with dissimilar properties. <span style="background-color:initial">This alteration has been reported in 1/4,112 breast cancer cases and 0/2,399 controls in a meta-analysis of the role of the ATM gene in breast cancer susceptibility (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This variant has also been detected in cohorts of patients with non-Hodgkin lymphoma, multiple primary tumors, and prostate cancer (Sipahimalani P et al. Int. J. Cancer. 2007 Nov;121:1967-75; Abida W et al. JCO Precis Oncol. 2017 Jul;2017; Whitworth J et al. Am. J. Hum. Genet. 2018 Jul;103:3-18).<span style="background-color:initial"> In functional studies this variant demonstrated an absence of kinase activity in vivo and in vitro, and increased sensitivity to ionizing radiation (Scott SP et al. Proc. Natl. Acad. Sci. U.S.A. 2002 Jan;99:925-30<span style="background-color:initial">). <span style="background-color:initial">Scott et al. also demonstrated the ability of the p.S2592C variant to interfere with wild-type kinase activity in a dominant negative fashion. <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000230322 SCV000283062 uncertain significance Ataxia-telangiectasia syndrome 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 2592 of the ATM protein (p.Ser2592Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs755009196, ExAC <0.01%). This variant has been observed in individuals affected with breast cancer, prostate cancer, or Non-Hodgkin's lymphoma (PMID: 11606401, 11805335, 19781682, 29909963, 28825054, 17640065). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 186713). Experimental in vitro studies have shown that this missense change abolishes ATM kinase activity and increases radiosensitivity (PMID: 11805335). 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 RCV000236197 SCV000293440 uncertain significance not provided 2021-07-01 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect: absent kinase activity, increased radiosensitivity in vitro, and dominant interfering effect (Scott 2002); Reported in individuals with breast or prostate cancer, but also in healthy controls (Dork 2001, Tavtigian 2009, Caminsky 2016, Abida 2017, Decker 2017); Not observed at significant frequency in large population cohorts (Lek 2016); 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: 27535533, 11805335, 29909963, 26898890, 28873162, 28779002, 28825054, 15450731, 20346647, 12511424, 21787400, 12969974, 12810666, 11839094, 16112413, 18568480, 12552566, 21910157, 16652348, 14643952, 15279808, 11606401, 19781682)
Color Health, Inc RCV000166355 SCV000687787 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-16 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000166355 SCV000992205 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic RCV000236197 SCV001713586 uncertain significance not provided 2020-05-28 criteria provided, single submitter clinical testing

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