ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.775G>A (p.Glu259Lys) (rs201559159)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212736 SCV000211443 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing This variant is denoted NBN c.775G>A at the cDNA level, p.Glu259Lys (E259K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been observed in at least one individual with familial pancreatic cancer (Chaffee 2018). NBN Glu259Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain (Damiola 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 NBN Glu259Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160783 SCV000217061 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000204371 SCV000259221 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 259 of the NBN protein (p.Glu259Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 182716). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Fulgent Genetics,Fulgent Genetics RCV000764784 SCV000895928 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000160783 SCV000903175 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781645 SCV000919856 uncertain significance not specified 2018-12-20 criteria provided, single submitter clinical testing Variant summary: NBN c.775G>A (p.Glu259Lys) results in a conservative amino acid change located in the second BRCT domain (IPR032429) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-06 in 301984 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.775G>A has not been reported in the literature in individuals affected with Nijmegen Breakage Syndrome, and no experimental evidence demonstrating an impact on protein function has been published. Three 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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