Submissions for variant NM_032043.3(BRIP1):c.3296T>G (p.Leu1099Arg)

gnomAD frequency: 0.00002  dbSNP: rs772709195

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165832	SCV000216579	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-22	criteria provided, single submitter	clinical testing	The p.L1099R variant (also known as c.3296T>G), located in coding exon 19 of the BRIP1 gene, results from a T to G substitution at nucleotide position 3296. The leucine at codon 1099 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477468	SCV000547271	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1099 of the BRIP1 protein (p.Leu1099Arg). This variant is present in population databases (rs772709195, gnomAD 0.006%). 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: 186266). 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 tolerated. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506104	SCV000600914	uncertain significance	not specified	2017-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165832	SCV000909746	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1099 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000291). This variant has been identified in 2/250866 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.
Baylor Genetics	RCV004567285	SCV005059234	uncertain significance	Familial cancer of breast	2024-03-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001357851	SCV005077990	uncertain significance	not provided	2024-03-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in patient(s) with prostate cancer (PMID: 36922933); This variant is associated with the following publications: (PMID: 33471991, 36922933)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357851	SCV001553440	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.L1099R variant was not identified in the literature nor was it identified in COSMIC. The variant was identified in dbSNP (ID: rs772709195) and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Color, and Quest Diagnostics). The variant was identified in control databases in 2 of 250866 chromosomes at a frequency of     0.000007972, and was observed only in the Latino population in 2 of 34588 chromosomes (freq: 0.00005782) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.L1099 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004539555	SCV004757140	uncertain significance	BRIP1-related disorder	2023-11-27	no assertion criteria provided	clinical testing	The BRIP1 c.3296T>G variant is predicted to result in the amino acid substitution p.Leu1099Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD, and is reported as having uncertain clinical significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186266/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.