ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.940G>A (p.Val314Met) (rs529845940)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130348 SCV000185199 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130348 SCV000537534 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Invitae RCV000464039 SCV000553111 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 314 of the NBN protein (p.Val314Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs529845940, ExAC 0.003%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 141727). 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: "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.
Integrated Genetics/Laboratory Corporation of America RCV000781636 SCV000919846 uncertain significance not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: NBN c.940G>A (p.Val314Met) alters a conserved nucleotide that results in a conservative amino acid change located in the Nibrin second BRCT domain (IPR032429) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 245998 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (2.8e-05 vs 2.50E-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.940G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrences with the pathogenic variant MUTYH c.536A>G (p.Y179C) was found in an internal specimen. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.