ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8921C>T (p.Pro2974Leu) (rs139379666)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122894 SCV000166152 likely benign Ataxia-telangiectasia syndrome 2018-01-09 criteria provided, single submitter clinical testing
GeneDx RCV000200970 SCV000209668 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.8921C>T at the cDNA level, p.Pro2974Leu (P2974L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was observed in individuals with breast cancer and in a child with acute lymphocytic leukemia (Oguchi 2003, Haiman 2013, Harismendy 2013). Functional assays performed by Oguchi et al. (2003) showed mRNA expression levels equivalent to wild type, partial rescue of the radiosensitive phenotype in fibroblasts, and reduction in phosphorylation activity; however, none of these assays showed complete loss of activity. ATM Pro2974Leu was observed at an allele frequency of 0.05% (9/18,866) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the FATC domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Pro2974Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159668 SCV000214151 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000122894 SCV000798159 uncertain significance Ataxia-telangiectasia syndrome 2018-02-28 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000200970 SCV000805634 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Color RCV000159668 SCV000910761 benign Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780903 SCV000918539 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: ATM c.8921C>T (p.Pro2974Leu) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 295220 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.8e-05 vs 0.004), allowing no conclusion about variant significance. c.8921C>T has been reported in the literature in affected individuals with leukemia, lymphoma, BrC, and glioma, without strong evidence for causality. One publication reports experimental evidence evaluating an impact on protein function and showed variant with partial rescue of the radiosensitive phenotype in fibroblasts and a partial reduction in phosphorylation activity. However, due to a lack of complete loss of activity, the correlation of these findings to in-vivo mechanism of disease is unclear. Also these studies have not been reproduced by multiple independent studies. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 VUS, 1 Likely benign). Based on the evidence outlined above, the variant was classified as VUS until more evidence becomes available.

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