Submissions for variant NM_032043.3(BRIP1):c.3389T>C (p.Ile1130Thr)

dbSNP: rs1057522432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441972	SCV000527675	uncertain significance	not provided	2016-05-05	criteria provided, single submitter	clinical testing	The I1130T variant in the BRIP1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I1130T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I1130T as a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775924	SCV000910413	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1130 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.
Invitae	RCV000820751	SCV000961478	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1130 of the BRIP1 protein (p.Ile1130Thr). 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: 386141). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000775924	SCV003859938	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	The p.I1130T variant (also known as c.3389T>C), located in coding exon 19 of the BRIP1 gene, results from a T to C substitution at nucleotide position 3389. The isoleucine at codon 1130 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444232	SCV004171502	uncertain significance	Familial cancer of breast	2023-10-19	criteria provided, single submitter	clinical testing	The BRIP1 c.3389T>C (p.Ile1130Thr) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with hereditary breast and ovarian cancer or Fanconi anemia. It is also absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004539857	SCV004770589	uncertain significance	BRIP1-related disorder	2023-11-07	criteria provided, single submitter	clinical testing	The BRIP1 c.3389T>C variant is predicted to result in the amino acid substitution p.Ile1130Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/386141/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.