ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.845C>G (p.Thr282Ser)

gnomAD frequency: 0.00001  dbSNP: rs45624635
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000116166 SCV000150075 uncertain significance not provided 2024-01-05 criteria provided, single submitter clinical testing Observed in individuals with breast, pancreatic, and colorectal cancer (PMID: 17033622, 34034685, 32658311); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30309722, 33471991, 32658311, 34034685, 17033622)
Ambry Genetics RCV000220423 SCV000273823 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-05 criteria provided, single submitter clinical testing The p.T282S variant (also known as c.845C>G), located in coding exon 6 of the BRIP1 gene, results from a C to G substitution at nucleotide position 845. The threonine at codon 282 is replaced by serine, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast cancer and/or pancreatic cancer (Seal S et al. Nat Genet, 2006 Nov;38:1239-41; Rapposelli IG et al. BMC Cancer, 2021 May;21:611). Additionally, this alteration was seen in 1/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This variant was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Color Diagnostics, LLC DBA Color Health RCV000220423 SCV000684307 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-28 criteria provided, single submitter clinical testing This missense variant replaces threonine with serine at codon 282 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 17033622) and in an individual affected with pancreatic cancer (PMID: 34034685). This variant has also been identified in 2/250948 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 RCV000693086 SCV000820941 uncertain significance Familial cancer of breast; Fanconi anemia complementation group J 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 282 of the BRIP1 protein (p.Thr282Ser). This variant is present in population databases (rs45624635, gnomAD 0.0009%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 34034685). ClinVar contains an entry for this variant (Variation ID: 128197). 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.
Sema4, Sema4 RCV000220423 SCV002529239 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-22 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000116166 SCV004220736 uncertain significance not provided 2023-05-04 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000008 (2/250948 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pancreatic cancer (PMID: 34034685 (2021)). In a large-scale breast cancer association study, the variant was observed in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000116166 SCV001549890 uncertain significance not provided no assertion criteria provided clinical testing The BRIP1 p.Thr282Ser variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in the following databases: dbSNP (ID: rs45624635) as "With Uncertain significance allele", ClinVar (3x uncertain significance), Clinvitae, and the Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 245670 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 5468 chromosomes (freq: 0.0002) and European in 1 of 111210 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr282 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.