Submissions for variant NM_032043.3(BRIP1):c.1643A>G (p.Tyr548Cys)

dbSNP: rs587782405

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131440	SCV000186423	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.Y548C variant (also known as c.1643A>G), located in coding exon 11 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1643. The tyrosine at codon 548 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in a patient affected with pancreatic ductal adenocarcinoma with a family history of rectal and prostate cancers (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230012	SCV000290981	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 548 of the BRIP1 protein (p.Tyr548Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 142358). 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 expected to disrupt BRIP1 protein function with a positive predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131440	SCV001734144	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 548 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Baylor Genetics	RCV004567134	SCV005059960	uncertain significance	Familial cancer of breast	2023-11-07	criteria provided, single submitter	clinical testing