Submissions for variant NM_032043.3(BRIP1):c.1192A>G (p.Ile398Val)

gnomAD frequency: 0.00001  dbSNP: rs786203967

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167500	SCV000218358	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The p.I398V variant (also known as c.1192A>G), located in coding exon 8 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1192. The isoleucine at codon 398 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545385	SCV000633540	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-06-15	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: 187745). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 398 of the BRIP1 protein (p.Ile398Val).
Color Diagnostics, LLC DBA Color Health	RCV000167500	SCV004362948	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 398 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 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.