ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1741T>G (p.Leu581Val) (rs876659822)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219147 SCV000276688 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000484735 SCV000572430 uncertain significance not provided 2016-12-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.1741T>G at the cDNA level, p.Leu581Val (L581V) at the protein level, and results in the change of a Leucine to a Valine (TTA>GTA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in a head and neck squamous cell carcinoma cell line (Nichols 2014). ATM Leu581Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Leu581Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain. 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 Leu581Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000219147 SCV000681995 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing
Invitae RCV000627927 SCV000748812 uncertain significance Ataxia-telangiectasia syndrome 2019-12-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 581 of the ATM protein (p.Leu581Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 232530). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030519 SCV001193467 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001174637 SCV001337846 uncertain significance not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: ATM c.1741T>G (p.Leu581Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251044 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.1741T>G in individuals affected with Breast Cancer 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.