Submissions for variant NM_032043.3(BRIP1):c.995G>A (p.Cys332Tyr)

dbSNP: rs876660521

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219492	SCV000278022	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	clinical testing	The p.C332Y variant (also known as c.995G>A), located in coding exon 7 of the BRIP1 gene, results from a G to A substitution at nucleotide position 995. The cysteine at codon 332 is replaced by tyrosine, an amino acid with highly dissimilar 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.
GeneDx	RCV000213448	SCV000279235	uncertain significance	not provided	2015-10-09	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.995G>A at the cDNA level, p.Cys332Tyr (C332Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRIP1 Cys332Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Cys332Tyr occurs at a position that is not conserved and is located in the Fe-S and helicase ATP-binding domains (Cantor 2011, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Cys332Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636095	SCV000757527	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-26	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 233613). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 332 of the BRIP1 protein (p.Cys332Tyr).
Color Diagnostics, LLC DBA Color Health	RCV000219492	SCV002052362	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 332 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251268 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.