ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3103C>T (p.Arg1035Cys) (rs45437094)

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Total submissions: 9
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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 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000590794 SCV000279384 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3103C>T at the cDNA level, p.Arg1035Cys (R1035C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported in at least one case of non-serous ovarian cancer and in one individual with invasive breast cancer (Ramus 2015, Easton 2016). BRIP1 Arg1035Cys was observed at an allele frequency of 0.4% (135/30782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located within the BRCA1 binding domain (Cantor 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Arg1035Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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
Integrated Genetics/Laboratory Corporation of America 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 RCV000129008 SCV000910605 likely benign Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.

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