ClinVar

Description

The NBN p.Glu564Lys variant was identified in 14 of 634 proband chromosomes (frequency: 0.022) from individuals or families with breast cancer and NBS (Kim 2015, Wang 2013). The variant was also identified in dbSNP (ID: rs72550742) as With Likely benign allele, ClinVar (classified as benign by GeneDx, Invitae; classified as likely benign by Ambry Genetics), Clinvitae (classified as benign by ClinVar, Invitae; classified as likely benign by ClinVar), Zhejiang Colon Cancer Database (1X), databases. The variant was not identified in Cosmic, LOVD 3.0, databases. The variant was identified in control databases in 218 of 276878 chromosomes at a frequency of 0.000787 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Glu564 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Nibrin functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
References (PMIDs): 25712764, 24349281