ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000129008 SCV000172905 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129008 SCV000910605 likely benign Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing
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
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.
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.
Invitae RCV000196034 SCV000253627 likely benign Familial cancer of breast; Fanconi anemia, complementation group J 2017-12-11 criteria provided, single submitter clinical testing

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