rs371185409

Description

DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.3079G>A, in exon 20 that results in an amino acid change, p.Glu1027Lys. This sequence change has been described in three individuals with colorectal cancer, or breast/ovarian cancer, or suspected Lynch syndrome-related cancer/polyps (PMIDs: 27978560, 25980754, 28528518). This sequence change has been described in the gnomAD database with a low frequency of 0.028% in the African/African American subpopulation (dbSNP rs371185409). The p.Glu1027Lys change affects a poorly conserved amino acid residue of the BRIP1 protein. The p.Glu1027Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu1027Lys change remains unknown at this time.

The p.E1027K variant (also known as c.3079G>A), located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 3079. The glutamic acid at codon 1027 is replaced by lysine, an amino acid with similar properties.This alteration has been reported in cohorts undergoing multi gene panel testing; in 1/85 Colombian women with hereditary breast and ovarian cancer and in 1/450 American individuals with colorectal cancer diagnosed under age 50 (Cock-Rada AM et al. Fam. Cancer 2018 Jan;17(1):23-30; Pearlman R et al. JAMA Oncol 2017 Apr;3(4):464-471). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with suspected Hereditary Breast and Ovarian Cancer or colorectal cancer and/or polyps (Yurgelun 2015, Pearlman 2017, Cock-Rada 2018); This variant is associated with the following publications: (PMID: 25980754, 27978560, 28528518, 31658756)