ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.584G>A (p.Ser195Asn)

dbSNP: rs1811862674
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310162 SCV001499750 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing NBN:c.584G>A variant absent from large population studies (GnomAd). It is predicted to abolish natural donor splice site of exon 5 by in silico splicing tools. Functional RNA study has shown that the variant causes significant splicing aberration - exon 5 skipping (PMID: 34439939). Therefore the variant was classified as likely pathogenic (ACMG/AMP: PS3, PM2, PP3).
Labcorp Genetics (formerly Invitae), Labcorp RCV001368080 SCV001564458 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 195 of the NBN protein (p.Ser195Asn). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1012201). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Genome-Nilou Lab RCV001368080 SCV002045963 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478769 SCV004222139 uncertain significance not provided 2023-06-16 criteria provided, single submitter clinical testing In the published literature, this variant has been reported to disrupt mRNA splicing by inducing out-of-frame exon 5 skipping (PMID: 34439939 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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