ClinVar

Description

The BRCA2 p.Thr1304Ala variant was not identified in the literature in a patient population. The variant was identified in dbSNP (ID: rs28897723 as "With other allele"), ClinVar (1x as benign by SCRP; 3x as likely benign by Ambry Genetics, GeneDx, and Invitae; and 4x as uncertain significance by Counsyl, BI, CHEO Genetics Diagnostic Laboratory, and at Sinai Health System), MutDB, LOVD 3.0 (2x), and UMD-LSDB (8x as unclassified variant). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 7 of 205258 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 4492 chromosomes (freq: 0.0002) and European in 6 of 95212 chromosomes (freq: 0.00006); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Thr1304 residue is not conserved in mammals and 5 of 5 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 5 of 5 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. This variant is classified as a variant of uncertain significance.