Submissions for variant NM_032043.3(BRIP1):c.1798T>C (p.Phe600Leu)

gnomAD frequency: 0.00003  dbSNP: rs745367580

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226896	SCV000290989	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 600 of the BRIP1 protein (p.Phe600Leu). This variant is present in population databases (rs745367580, gnomAD 0.002%). 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: 241631). 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.
Ambry Genetics	RCV001013216	SCV001173771	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-30	criteria provided, single submitter	clinical testing	The p.F600L variant (also known as c.1798T>C), located in coding exon 12 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1798. The phenylalanine at codon 600 is replaced by leucine, 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.
Color Diagnostics, LLC DBA Color Health	RCV001013216	SCV001341804	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 600 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282746 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.
GeneDx	RCV004721318	SCV005327416	uncertain significance	not provided	2023-11-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed only in controls from a case-control study of breast cancer (PMID: 26921362); This variant is associated with the following publications: (PMID: 24121792, 21822268, 32930150, 26921362)
PreventionGenetics, part of Exact Sciences	RCV004732808	SCV005363768	uncertain significance	BRIP1-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The BRIP1 c.1798T>C variant is predicted to result in the amino acid substitution p.Phe600Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/241631/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.