ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3793T>C (p.Phe1265Leu) (rs371526361)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167365 SCV000218217 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000167365 SCV000913928 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000483445 SCV000567223 uncertain significance not provided 2016-06-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.3793T>C at the cDNA level, p.Phe1265Leu (F1265L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Phe1265Leu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Phe1265Leu occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Phe1265Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780912 SCV000918558 uncertain significance not specified 2018-08-31 criteria provided, single submitter clinical testing Variant summary: ATM c.3793T>C (p.Phe1265Leu) results in a non-conservative amino acid change in 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 2.5e-05 in 276924 control chromosomes. 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.3793T>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 RCV000205586 SCV000259901 uncertain significance Ataxia-telangiectasia syndrome 2018-08-21 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 1265 of the ATM protein (p.Phe1265Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs371526361, 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: 187620). 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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