ClinVar

Description

Variant summary: NBN c.284A>G (p.Asp95Gly) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain 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 3.6e-05 in 277122 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (3.6e-05 vs 0.0025), allowing no conclusion about variant significance. c.284A>G has been reported in the literature in individuals affected with breast cancer (Hauke_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.