ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3478G>C (p.Val1160Leu) (rs567344545)

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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 RCV000221290 SCV000274708 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000218210 SCV000278820 uncertain significance not provided 2016-03-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.3478G>C at the cDNA level, p.Val1160Leu (V1160L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val1160Leu was not observed at a significant allele frequency in 1000 Genomes. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Val1160Leu occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the beta-adaptin interaction domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Val1160Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000474968 SCV000546913 uncertain significance Ataxia-telangiectasia syndrome 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1160 of the ATM protein (p.Val1160Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs567344545, ExAC 0.001%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 230990). 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.
Color RCV000221290 SCV000682133 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780901 SCV000918537 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: ATM c.3478G>C (p.Val1160Leu) 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 8.1e-06 in 246156 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 4.00e-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3478G>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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