ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5185G>C (p.Val1729Leu) (rs3092907)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115206 SCV000185913 likely benign Hereditary cancer-predisposing syndrome 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Does not segregate with disease in family study (genes with incomplete penetrance),No disease association in small case-control study,Other data supporting benign classification
Color RCV000115206 SCV000910687 likely benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
GeneDx RCV000589866 SCV000149115 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.5185G>C at the cDNA level, p.Val1729Leu (V1729L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). This variant has been reported in at least two individuals with Ataxia-telangiectasia, including one individual with cerebellar ataxia who carried this variant in the homozygous state but was also found to carry a pathogenic ATM variant in the homozygous state (Magliozzi 2006, Coutelier 2018). ATM Val1729Leu has also been observed in individuals with breast, colorectal, or uterine cancer as well as in unaffected individuals (Thorstenson 2001, Ricker 2017, Tiao 2017, Hauke 2018, Yehia 2018). Additionally, ATM Val1729Leu was not seen in 4,112 breast cancer patients, but was identified in 1/2,399 control subjects in a large meta-analysis (Tavtigian 2009). This variant was observed at an allele frequency of 0.02% (6/34,416) in individuals of Latino ancestry in large population cohorts (Lek 2016). ATM Val1729Leu 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 Val1729Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589866 SCV000694300 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing Variant summary: c.5185G>C affects a conserved nucleotide, resulting in amino acid change from Val to Leu. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). The variant is located 8 nucleotides from the inton/exon boundary of exon 35, however 5/5 in silico tools via Alamut predict no significant effect on canonical splicing site and 1/5 in silico tools predict loss of a cryptic splicing donor and acceptor sites. ESEfinder predicts a gain of binding motif for RNA splicing enhancer. These in silico predictions have not been validated by any in vivo/vitro functional studies. This variant was found in 10/121910 control chromosomes at a frequency of 0.0000000082, which does not significantly exceed the predicted maximal expected frequency of a pathogenic allele (0.0039528). The variant has not been reported in affected individuals in the literature, however has been reported in an unaffected control individuals and was considered as a polymorphism (Thorstenson_2001, Magliozzi_2006). Two reputable databases have classified the variant as "likely benign" and one classified this variant as VUS, all without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS), until additional information becomes available.
Invitae RCV000204511 SCV000261222 uncertain significance Ataxia-telangiectasia syndrome 2018-06-14 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1729 of the ATM protein (p.Val1729Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs3092907, ExAC 0.02%). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 17124347), as well as in unaffected individuals (PMID: 11443540, 19781682). ClinVar contains an entry for this variant (Variation ID: 127401). 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 C0"). 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.
Mendelics RCV000204511 SCV000838552 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115206 SCV000787871 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-23 no assertion criteria provided clinical testing

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.