ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6537T>G (p.Ile2179Met) (rs146243469)

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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 RCV000165775 SCV000216520 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000205267 SCV000260111 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 2179 of the ATM protein (p.Ile2179Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs146243469, ExAC 0.06%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186221). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000590569 SCV000292476 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.6537T>G at the cDNA level, p.Ile2179Met (I2179M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATT>ATG). This variant has been reported in an individual of African ancestry with breast cancer, and in a breast/prostate cancer case-control study, with no significant difference in frequency between case and controls (p=0.28) (Haiman 2013, Tung 2015). ATM Ile2179Met was observed at an allele frequency of 0.05% (13/24038) 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ile2179Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165775 SCV000682347 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590569 SCV000694326 uncertain significance not provided 2015-12-14 criteria provided, single submitter clinical testing Variant summary: c.6537T>G affects a non-conserved nucleotide, resulting in amino acid change from Ile to Met. 3/5 in-silico tools predict this variant to be damaging. This variant was found in 6/121406 control chromosomes at a frequency of 0.0000494, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0005001). In addition, one clinical laboratory classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590569 SCV000706961 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing
Mendelics RCV000205267 SCV000838575 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764937 SCV000896109 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing

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