ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.3103C>T (p.Arg1035Cys)

gnomAD frequency: 0.00006  dbSNP: rs45437094
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129008 SCV000172905 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-20 criteria provided, single submitter clinical testing The p.R1035C variant (also known as c.3103C>T), located in coding exon 19 of the BRIP1 gene, results from a C to T substitution at nucleotide position 3103. The arginine at codon 1035 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers. (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been detected in 2/189 Turkmen patients with esophageal squamous cell carcinoma (Akbari MR et al. Hum. Genet. 2011 May;129:573-82) and in a Caucasian patient diagnosed with a pancreatic neuroendocrine tumor (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is poorly 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.
Invitae RCV001081667 SCV000253627 likely benign Familial cancer of breast; Fanconi anemia complementation group J 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000590794 SCV000279384 likely benign not provided 2021-01-29 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 26921362, 25722345, 21279724, 17033622)
Counsyl RCV000410906 SCV000490057 uncertain significance Fanconi anemia complementation group J 2016-10-21 criteria provided, single submitter clinical testing
Counsyl RCV000412441 SCV000490058 uncertain significance Neoplasm of ovary 2016-10-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590794 SCV000699713 benign not provided 2016-05-27 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.3103C>T (p.Arg1035Cys) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 72/125562 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0039976 (66/16510). This frequency is about 64 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), highly suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. Additionally, the variant of interest was found to co-occur with a likely pathogenic PALB2 variant, c.829_832delGACC, in one internal LCA specimen. Furthermore, one clinical diagnostic laboratory recently classified this variant as likely benign. Taken together, this variant is classified as Benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000590794 SCV000885118 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing The p.Arg1035Cys variant (rs45437094) has been reported in the medical literature in at least one case of non-serous ovarian cancer (Ramus 2015). The p.Arg1035Cys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.48% in the South Asian population (identified in 135 out of 30,782 chromosomes; 0 homozygotes), and is listed in ClinVar (likely benign/uncertain significance; Variant ID: 140819). The arginine at codon 1,035 is weakly conserved considering 12 species (Alamut software v2.9.0), and computational analyses suggest that this variant does not affect the Brip1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). While the p.Arg1035Cys appears to be a benign polymorphism in the South Asian population, the available information is insufficient to determine the clinical significance with certainty.
Color Diagnostics, LLC DBA Color Health RCV000129008 SCV000910605 likely benign Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000410906 SCV001284863 uncertain significance Fanconi anemia complementation group J 2018-01-15 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800423 SCV002046314 benign not specified 2020-10-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001800423 SCV002068138 uncertain significance not specified 2020-12-03 criteria provided, single submitter clinical testing DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.3103C>T, in exon 20 that results in an amino acid change, p.Arg1035Cys. This sequence change does not appear to have been previously described in patients with BRIP1-related disorders and has been described in the gnomAD database with a frequency of 0.44% in the South Asian sub-population (dbSNP rs45437094). The p.Arg1035Cys change affects a poorly conserved amino acid residue located in a domain of the BRIP1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1035Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1035Cys change remains unknown at this time.
Sema4,Sema4 RCV000129008 SCV002533677 likely benign Hereditary cancer-predisposing syndrome 2021-09-16 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355322 SCV001550180 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Arg1035Cys variant was identified in 1 of 26426 proband chromosomes (frequency: 3.78 E-05) from individuals or families with breast cancer and was not identified in 10484 control chromosomes from healthy individuals (Easton 2016). The variant was also identified in the following databases: dbSNP (ID: rs45437094) as With Uncertain significance allele, ClinVar with conflicting interpretations of pathogenicity (as likely benign by Invitae, and as uncertain significance by Ambry Genetics, Gene Dx and Counsyl), Clinvitae (5x), and Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 149 of 277168 chromosomes at a frequency of 0.000538 in the following populations: South Asian in 135 of 30782 chromosomes (freq. 0.004), Other in 149 of 6466 chromosomes (freq. 0.00016), European (Non-Finnish) in 11 of 126676 chromosomes (freq. 0.000087), East Asian in 1 of 18858 chromosomes (freq. 0.00005), and Latino in 1 of 34418 chromosomes (freq. 0.000029) (Genome Aggregation Consortium Feb 27, 2017). The p.Arg1035Cys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001800423 SCV002551152 uncertain significance not specified 2022-05-17 no assertion criteria provided clinical testing

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