ClinVar

Description

The BRCA2 p.Asn830Asp variant was identified in 2 of 3744 proband chromosomes (frequency: 0.0005) from individuals or families with breast or ovarian cancer (Tung 2015, Rajkumar 2015). The variant was also identified in dbSNP (ID: rs574039421) as "With Uncertain significance allele", ClinVar (classified as likely benign by GeneDx; as uncertain significance by Invitae, Ambry Genetics, Color and Counsyl), and in UMD-LSDB (1x as unclassified variant). The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or Zhejiang University, databases. The variant was identified in control databases in 25 of 235966 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 25 of 27740 chromosomes (freq: 0.0009), but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn830 residue is not conserved in mammals and 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) 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.