Description
The NBN p.Pro266Leu variant was identified in 14 of 2874 proband chromosomes (frequency: 0.005) from individuals or families with various types of cancer and was present in 4 of 1362 control chromosomes (frequency: 0.003) from healthy individuals (Berg 2013, Bodian 2014, Desjardins 2009, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs769420) as "With Benign allele", ClinVar (5x benign), Clinvitae (4x benign), and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic or the LOVD 3.0 database. The variant was identified in control databases in 771 of 276952 chromosomes (11 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 705 of 24006 chromosomes (freq: 0.03), Other in 5 of 6454 chromosomes (freq: 0.0008), Latino in 44 of 34382 chromosomes (freq: 0.001), European in 4 of 126556 chromosomes (freq: 0.00003), East Asian in 9 of 18864 chromosomes (freq: 0.0005), and South Asian in 4 of 30776 chromosomes (freq: 0.0001). The variant was not observed in the Ashkenazi Jewish or Finnish populations. Various studies utilizing computational algorithms, personal disease history, and family disease history have been performed; most of these studies conclude the variant is not associated with cancer (Berg 2013, Berardinelli 2013, Bodian 2014, Desjardins 2009, Gao 2013, Yurgelun 2015). The p.Pro266 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the leucine variant may impact the protein; however, this information is not predictive enough to assume 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. 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.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | unknown | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
