ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8668C>G (p.Leu2890Val) (rs587779874)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115268 SCV000149177 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.8668C>G at the cDNA level, p.Leu2890Val (L2890V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has been reported as a somatic mutation in lymphoid neoplasms, but has not been reported as a germline pathogenic variant or benign variant to our knowledge (COSMIC, Skowronska 2012, Navrkalova 2013). ATM Leu2890Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 and is unlikely to affect protein integrity. ATM Leu2890Val occurs at a position that is well conserved across species and is located in the kinase domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider ATM Leu2890Val to be a variant of uncertain significance. This variant appears to be mosaic, as the variant allele was present but underrepresented in comparison to the normal allele. This result was confirmed using alternate, non-overlapping primers, making it unlikely that this result is due to preferential amplification of the normal allele. Therefore, this variant is interpreted to be present in some, but not all, cells in this peripheral blood specimen. Neither Sanger nor Next Generation sequencing is a quantitative test; thus, it is not possible to determine more precisely the level of mosaicism in this specimen. Moreover, the level of mosaicism may be different in other tissues. As somatic mosaicism generally results from a post-zygotic event, parents and siblings are not likely at risk to carry this mosaic mutation. Germline mosaicism and transmission to the offspring of this patient, however, cannot be excluded. Given that ATM Leu2890Val has only been reported as a somatic variant in association with lymphoid neoplasms and was detected at low levels in this individual, we cannot definitively determine if the variant identified represents mosaicism or is due to an underlying lymphoid neoplasm.
Invitae RCV000628131 SCV000749024 uncertain significance Ataxia-telangiectasia syndrome 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 2890 of the ATM protein (p.Leu2890Val). 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: 127462). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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