ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.468A>C (p.Lys156Asn) (rs730881858)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160796 SCV000211461 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing This variant is denoted NBN c.468A>C at the cDNA level, p.Lys156Asn (K156N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Lys156Asn was observed at an allele frequency of 0.11% (37/33,574) in individuals of Latino ancestry in large population cohorts (Lek 2016). Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. NBN Lys156Asn is located in the BRCT1 domain (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NBN Lys156Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000222254 SCV000275100 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000456204 SCV000553116 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 156 of the NBN protein (p.Lys156Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs730881858, ExAC 0.1%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 182729). 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: "Possibly 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.
Color RCV000222254 SCV000685786 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000160796 SCV000806442 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781643 SCV000919854 uncertain significance not specified 2018-09-24 criteria provided, single submitter clinical testing Variant summary: NBN c.468A>C (p.Lys156Asn) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 246028 control chromosomes (gnomAD), exclusively reported within the Latino subpopulation at a frequency of 0.0011, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.0011 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.468A>C in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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