ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2747A>G (p.Asn916Ser) (rs765043916)

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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 RCV000220288 SCV000273368 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000226024 SCV000284420 uncertain significance Neurofibromatosis, type 1 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 916 of the NF1 protein (p.Asn916Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs765043916, ExAC 0.003%). This variant has not been reported in the literature in individuals with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 229977). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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.
PreventionGenetics,PreventionGenetics RCV000679381 SCV000806268 uncertain significance not provided 2016-11-09 criteria provided, single submitter clinical testing
GeneDx RCV000679381 SCV000808688 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2747A>G at the cDNA level, p.Asn916Ser (N916S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in an infant with <5 cafe-au-lait macules and a CNS glioma, and was also observed to segregate with cafe-au-lait macules in three affected family members in another kindred (Koczkowska 2018). NF1 Asn916Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein domain (Xu 1990, Luo 2014). 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 NF1 Asn916Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761186 SCV000891102 uncertain significance Acute monocytic leukemia; Acute monoblastic leukemia 2017-04-03 no assertion criteria provided clinical testing

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