rs587782808

Description

This sequence change replaces glutamic acid with lysine at codon 1022 of the BRIP1 protein (p.Glu1022Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs587782808, ExAC 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26315354, 26921362). ClinVar contains an entry for this variant (Variation ID: 142900). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The BRIP1 p.Glu1022Lys variant was identified in 4 of 33174 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer and was present in 9 of 17458 control chromosomes (frequency: 0.0005) from healthy individuals (Ramus 2015, Easton 2016). The variant was also identified in dbSNP (ID: rs587782808) as "With Uncertain significance allele", in ClinVar (classified as likely benign by Ambry Genetics and uncertain significance by Invitae). The variant was identified in control databases in 3 of 246220 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15304 chromosomes (freq: 0.000065), European Non-Finnish in 2 of 111680 chromosomes (freq: 0.00002), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu1022 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. This variant is classified as a variant of uncertain significance.

In silico models in agreement (benign);Other strong data supporting benign classification

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26315354, 26921362)