ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.254A>G (p.Asn85Ser) (rs587780095)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214236 SCV000273223 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (benign)
Color RCV000214236 SCV000902943 likely benign Hereditary cancer-predisposing syndrome 2016-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000115791 SCV000149700 uncertain significance not provided 2014-12-15 criteria provided, single submitter clinical testing This variant is denoted NBN c.254A>G at the cDNA level, p.Asn85Ser (N85S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Asn85Ser 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 Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. NBN Asn85Ser occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether NBN Asn85Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000231493 SCV000287467 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 85 of the NBN protein (p.Asn85Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587780095, ExAC 0.07%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 127868). 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.

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