Submissions for variant NM_032043.3(BRIP1):c.604A>G (p.Ile202Val)

dbSNP: rs778275257

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469045	SCV000547227	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 202 of the BRIP1 protein (p.Ile202Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407787). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000573114	SCV000668872	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-16	criteria provided, single submitter	clinical testing	The p.I202V variant (also known as c.604A>G), located in coding exon 5 of the BRIP1 gene, results from an A to G substitution at nucleotide position 604. The isoleucine at codon 202 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved on limited sequence alignment. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573114	SCV000684291	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 202 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 BRIP1-related disorders 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.
GeneDx	RCV001591084	SCV001824504	uncertain significance	not provided	2019-11-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000573114	SCV002533727	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Baylor Genetics	RCV003476062	SCV004211317	uncertain significance	Familial cancer of breast	2022-12-19	criteria provided, single submitter	clinical testing