ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7475T>G (p.Leu2492Arg) (rs56399857)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115252 SCV000172858 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488003 SCV000574909 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
Clinical Cancer Genetics and Family Consultants,Athens Medical Center RCV000786770 SCV000924666 likely pathogenic Familial cancer of breast 2019-06-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.7475T>G at the cDNA level, p.Leu2492Arg at the protein level, and is a non-conservative amino acid change located in the PIK-related kinase, FAT domain (Stracker 2013) of the encoded protein sequence. Five of five in silico tools predict a damaging effect of this variant on protein function. This is a rare variant (ExAC 0.00006), and has been reported in various cancers (Lu 2015, Greenman 2007, Berstein 2010). We report this variant to occur in two sisters, both heterozygotes, with breast cancer, of 47 and 50 years old. The second one also developed thyroid cancer at the age of 55. A third sister tested, is a healthy non-carrier at the age of 59 years old. The family on the paternal side included one case of breast cancer at the age of 70 years old, and another one with breast and thyroid cancer at the age of 40 and 65 years old respectively. For these reasons, this variant may be causative of disease in this family and we classify it as probably pathogenic.
Color RCV000115252 SCV000537541 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing
Counsyl RCV000195623 SCV000800168 uncertain significance Ataxia-telangiectasia syndrome 2018-05-24 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000195623 SCV000745132 uncertain significance Ataxia-telangiectasia syndrome 2017-05-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000195623 SCV000732995 uncertain significance Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000488003 SCV000706050 uncertain significance not provided 2017-02-21 criteria provided, single submitter clinical testing
GeneDx RCV000488003 SCV000149161 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.7475T>G at the cDNA level, p.Leu2492Arg (L2492R) at the protein level, and results in the change of a Leucine to an Arginine (CTT>CGT). This variant has been observed in individuals with breast cancer (Decker 2017, Hauke 2018), colon cancer (Yurgelun 2017), and other cancers (Greenman 2007, Lu 2015, Tiao 2017, Yehia 2018). ATM Leu2492Arg was observed at an allele frequency of 0.02% (27/126,540) in individuals of European ancestry in large population cohorts (Lek 2016). ATM Leu2492Arg is located within the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether ATM Leu2492Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115252 SCV000821871 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115252 SCV000679694 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780920 SCV000918571 uncertain significance not specified 2018-10-19 criteria provided, single submitter clinical testing Variant summary: ATM c.7475T>G (p.Leu2492Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 277034 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0001 vs 0.004), allowing no conclusion about variant significance. In addition, the variant was found in 5/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.7475T>G has been reported in the literature in individuals affected with lung cancer, glioblastoma, leukemia, breast cancer, and Lynch syndrome associated cancers, and also in healthy controls (Bernstein_2010, Greenman_2007, Lu_2015, Tiao_2017, Young_2016, Yurgelun_2015, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000195623 SCV000254145 uncertain significance Ataxia-telangiectasia syndrome 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 2492 of the ATM protein (p.Leu2492Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs56399857, ExAC 0.01%). This variant has been reported in individuals affected with chronic lymphocytic leukemia (PMID: 28652578), suspected Lynch syndrome (PMID: 25980754), glioblastoma (PMID: 26689913), and breast cancer (Invitae). However, in the latter individual a pathogenic allele was also identified in ATM, which suggests that this c.7475T>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 127446). 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. 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.

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