Submissions for variant NM_032043.3(BRIP1):c.1897A>C (p.Ile633Leu)

dbSNP: rs765314472

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164796	SCV000215476	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.I633L variant (also known as c.1897A>C), located in coding exon 12 of the BRIP1 gene, results from an A to C substitution at nucleotide position 1897. The isoleucine at codon 633 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well 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	RCV000217145	SCV000279945	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24807215)
Color Diagnostics, LLC DBA Color Health	RCV000164796	SCV000292193	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 633 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 been reported in three individuals affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000185). This variant has been identified in 9/251438 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457977	SCV000547297	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 633 of the BRIP1 protein (p.Ile633Leu). This variant is present in population databases (rs765314472, gnomAD 0.03%). 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: 185386). 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 with a negative 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000999642	SCV001134996	uncertain significance	Familial cancer of breast	2019-11-14	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 13 of the BRIP1 gene that results in the amino acid substitution of Leucine for Isoleucine at codon 633 was detected. It is documented as variant of uncertain significance in Clinvar database. The observed variant c.1897A>C (p.Thr279Ile) has not been reported in the 1000 Genomes and has a minor alllele frequency of 0.004% in the ExAC database. The in silico prediction of the variant are damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, Thr279Ile variant meets our criteria to be classified as a variant of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493473	SCV004242901	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing