Submissions for variant NM_032043.3(BRIP1):c.388G>A (p.Glu130Lys)

dbSNP: rs876658860

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218899	SCV000274650	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	The p.E130K variant (also known as c.388G>A), located in coding exon 4 of the BRIP1 gene, results from a G to A substitution at nucleotide position 388. The glutamic acid at codon 130 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000218899	SCV000903854	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 130 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354). This variant has been identified in 1/250896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047162	SCV001211099	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 130 of the BRIP1 protein (p.Glu130Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 230947). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469074	SCV002766481	uncertain significance	not specified	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.388G>A (p.Glu130Lys) results in a conservative amino acid change located in the helicase-like, DEXD box c2 type of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250896 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in an individual affected with ovarian cancer (Ramus_2015), although no clear association between the variant and disease was described. No experimental evidence demonstrating the impact of c.388G>A on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV004567544	SCV005059268	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing