ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7313C>T (p.Thr2438Ile) (rs147604227)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115246 SCV000186496 likely benign Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign) ,No disease association in appropriately sized case-control study(ies),Insufficient or conflicting evidence,Subpopulation frequency in support of benign classification,Other data supporting benign classification
Color RCV000115246 SCV000902700 benign Hereditary cancer-predisposing syndrome 2015-09-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589408 SCV000861415 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515201 SCV000611370 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000589408 SCV000149155 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.7313C>T at the cDNA level, p.Thr2438Ile (T2438I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been reported as neutral based on the fact that it was found to occur in cis with a truncating variant in a patient with Ataxia-telangiectasia (Li 2000). ATM Thr2438Ile was also reported in at least two individuals undergoing multigene cancer panel testing based on a history of early-onset breast cancer or a Lynch-syndrome associated cancer and/or polyps (Maxwell 2014, Yurgelun 2015). Hirsch et al. (2008) did not identify this variant in a series of 31 breast cancer cases of African American ancestry, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 0/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Thr2438Ile was observed at an allele frequency of 0.20% (47/24,004) 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 Thr2438Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115246 SCV000576463 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589408 SCV000694348 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The ATM c.7313C>T (p.Thr2438Ile) variant located in the PIK-related kinase, FAT domain (via InterPro) causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 16/116078 (1/7256), predominantly in the African cohort, 16/9978 (1/623), which exceeds the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/2000 for Breast Cancer. Therefore, suggesting this variant is a polymorphism found in population(s) of African origin. The variant of interest has been reported in multiple affected individuals (BrC, Lynch Syndrome and A-T) via publications, including an Ataxia-Telangiectasia pt that the variant was observed in cis with another pathogenic ATM variant. In at-least one such report, it was found not to have an associated risk with BrC (Haiman_PLOS Genetics_2013). This study concluded that there is no support for the role of protein-coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. In addition, multiple reputable clinical laboratories cite the variant as "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest was classified as a "Variant of Uncertain Significance - Possibly Benign, " until additional information becomes available.
Invitae RCV000200256 SCV000254142 likely benign Ataxia-telangiectasia syndrome 2018-01-09 criteria provided, single submitter clinical testing
Mendelics RCV000200256 SCV000838591 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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