ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2836A>G (p.Met946Val) (rs587781992)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130397 SCV000185256 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130397 SCV000902852 likely benign Hereditary cancer-predisposing syndrome 2016-05-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515251 SCV000611353 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000485729 SCV000568002 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.2836A>G at the cDNA level, p.Met946Val (M946V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Met946Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Met946Val is not located in a known functional domain. 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 Met946Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779792 SCV000916594 uncertain significance not specified 2018-09-14 criteria provided, single submitter clinical testing Variant summary: ATM c.2836A>G (p.Met946Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277036 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2836A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000168097 SCV000218753 uncertain significance Ataxia-telangiectasia syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 946 of the ATM protein (p.Met946Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs587781992, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141763). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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