Submissions for variant NM_032043.3(BRIP1):c.1208G>A (p.Arg403Gln)

gnomAD frequency: 0.00001  dbSNP: rs786202780

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165766	SCV000216511	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.R403Q variant (also known as c.1208G>A), located in coding exon 8 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1208. The arginine at codon 403 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphocytic leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This alteration was also detected on a 25-gene panel test in a woman with Latin American/Caribbean ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). 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	RCV000459631	SCV000547286	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 403 of the BRIP1 protein (p.Arg403Gln). This variant is present in population databases (rs786202780, gnomAD 0.008%). 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: 186213). 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.
GeneDx	RCV000483464	SCV000569510	uncertain significance	not provided	2024-05-14	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; This variant is associated with the following publications: (PMID: 29338689, 37306523, 36922933, 26580448, 25186627)
Color Diagnostics, LLC DBA Color Health	RCV000165766	SCV000906531	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 403 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 5/282362 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483464	SCV005623257	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535117	SCV004765941	uncertain significance	BRIP1-related disorder	2023-10-26	no assertion criteria provided	clinical testing	The BRIP1 c.1208G>A variant is predicted to result in the amino acid substitution p.Arg403Gln. This variant has been reported in two individuals, one with early-onset breast cancer (Tung et al. 2015. PubMed ID: 25186627) and another with acute lymphoblastic leukemia (ALL) (Zhang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59876593-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186213/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.