rs28997573

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1148 of the BRIP1 protein (p.Asp1148Glu). This variant is present in population databases (rs28997573, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome, ovarian cancer, breast cancer, and renal clear cell carcinoma (PMID: 25186627, 25980754, 26315354, 26689913). ClinVar contains an entry for this variant (Variation ID: 133758). 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 glutamic acid 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with BRIP1-related and other cancers but also in healthy controls (Seal 2006, Tung 2015, Ramus 2015, Yurgelun 2015, Easton 2016); This variant is associated with the following publications: (PMID: 20159562, 21127055, 23555315, 25980754, 17033622, 26921362, 26689913, 26315354, 24728327, 25186627)

Variant summary: The BRIP1 c.3444C>A (p.Asp1148Glu) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 15/131898 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000165 (11/66494). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The varaint was reported in the literature in BrC/OvC patients, without strong evidence for causality, as well as in a Lynch syndrome patient who carried a potentially pathogenic MLH1 variant (c.1989+3dupC; Yurgelun_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS, while one classified it as likely benign. Due to the relatively high frequency of the variant in the general population, multiple in silico tools predict benign outcome, as well as the co-occurrence in a patient with a potentially pathogenic variant, this variant has been classified as possibly benign variant until additional evidence becomes available.

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

Variant interpreted as Uncertain significance and reported on 09-15-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.