ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2096A>G (p.Glu699Gly) (rs147934285)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159606 SCV000214158 benign Hereditary cancer-predisposing syndrome 2014-12-04 criteria provided, single submitter clinical testing
Color RCV000159606 SCV000687354 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
Counsyl RCV000204474 SCV000799620 uncertain significance Ataxia-telangiectasia syndrome 2018-04-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174438 SCV000225742 benign not specified 2014-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000174438 SCV000209590 likely benign not specified 2017-09-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000589581 SCV000694208 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.2096A>G (p.Glu699Gly) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 23/120876 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0021459 (22/10252). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant was reported in two individuals being tested for Lynch syndrome and in an endometrial cancer patient however without strong evidence for causality such as co-segregation. A GWAS study reported the variant to increase the risk of breast cancer with an OR of 3.065, which is does not represent a strong indication for pathogenicity (according to ACMG guidelines, OR >5 can be considered as a strong evidence for pathogenicity). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, the pathogenicity or neutrality of the variant cannot be established based on available evidence, therefore this variant is classified as VUS.
Invitae RCV000204474 SCV000261092 uncertain significance Ataxia-telangiectasia syndrome 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 699 of the ATM protein (p.Glu699Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs147934285, ExAC 0.2%). This variant has been reported in two individuals undergoing testing for Lynch syndrome (PMID: 25980754), an individual with breast cancer (PMID: 26976419), and an individual with endometrial cancer (PMID: 27443514). In a large meta-analysis studying the association of ATM missense variants with the risk of breast cancer, this c.2096A>G substitution showed no evidence for increased cancer risk (0/2,531 cases vs. 1/2,245 controls) (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 181850). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
PreventionGenetics RCV000174438 SCV000301656 likely benign not specified criteria provided, single submitter clinical testing

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