ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with pancreatic cancer (Shindo 2017); This variant is associated with the following publications: (PMID: 28767289)

The BUB1B c.3094A>C (p.Asn1032His) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 including 1 homozygote (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with mosaic variegated aneuploidy syndrome. In summary, the evidence currently available is insufficient to determine the role of this variant in mosaic variegated aneuploidy syndrome. It has therefore been classified as of uncertain significance.

The BUB1B p.Asn1032His variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs34700927) as "With Uncertain significance allele" as well as in Clinvar as uncertain significance by one submitter, Invitae. The condition associated with this variant is Mosaic variegated aneuploidy syndrome. In the LOVD 3.0 database, the variant is classified as likely benign and probably does not affect protein function according to three submitters. The variant was identified in control databases in 201 of 282894 chromosomes (1 homozygous) at a frequency of 0.000711 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 172 of 129200 chromosomes (freq: 0.001331), Other in 8 of 7226 chromosomes (freq: 0.001107), Latino in 10 of 35440 chromosomes (freq: 0.000282), European (Finnish) in 5 of 25122 chromosomes (freq: 0.000199), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), African in 4 of 24970 chromosomes (freq: 0.00016); it was not observed in the East Asian, South Asian, populations. The variant was also identified in the following databases: the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium (August 8th 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Asn1032 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The BUB1B c.3094A>C variant is predicted to result in the amino acid substitution p.Asn1032His. To our knowledge, this variant has not been reported in the literature in an individual with mosaic variegated aneuploidy syndrome (MVA). This variant has been reported in six individuals in a large pancreatic cancer cohort (Shindo et al. 2017. PubMed ID: 28767289), but it is unclear at this time whether heterozygous germline BUB1B variants are associated with an increased risk of pancreatic cancer. This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygote, and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/403757/). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence.