ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1735C>T (p.Arg579Cys) (rs28997571)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212315 SCV000150039 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1735C>T at the cDNA level, p.Arg579Cys (R579C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported in individuals with breast cancer, an individual with familial colorectal cancer and melanoma who also harbored the APC p.Ile1307Lys risk allele, as well as unaffected controls (Tung 2015, Easton 2016, Yurgelun 2017). BRIP1 Arg579Cys was observed at an allele frequency of 0.1% (24/24,026) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg579Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116130 SCV000186447 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000196018 SCV000255150 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 579 of the BRIP1 protein (p.Arg579Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs28997571, ExAC 0.06%). This variant has been reported in individuals affected with breast cancer, colorectal cancer, and pancreatic cancer, as well as in unaffected individuals (PMID: 25186627, 26921362, 28135145, 28767289). ClinVar contains an entry for this variant (Variation ID: 128162). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000412043 SCV000490015 uncertain significance Fanconi anemia, complementation group J 2016-09-27 criteria provided, single submitter clinical testing
Counsyl RCV000410174 SCV000490016 uncertain significance Neoplasm of ovary 2016-09-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212315 SCV000807123 uncertain significance not provided 2016-11-09 criteria provided, single submitter clinical testing
Mendelics RCV000412043 SCV000839377 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212315 SCV000885123 uncertain significance not provided 2018-05-06 criteria provided, single submitter clinical testing The BRIP1 c.1735C>T; p.Arg579Cys variant (rs28997571) is reported in the germline of individuals with different cancer types, including breast cancer (Easton 2016, Shindo 2017, Tung 2015, Yurgelun 2017), but is also reported in healthy controls (Easton 2016). This variant is reported as uncertain by multiple laboratories in ClinVar (Variation ID: 128162). It is found in the general population with an overall allele frequency of 0.01% (35/277158 alleles) in the Genome Aggregation Database. The arginine at codon 579 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Arg579Cys variant is uncertain at this time. REFERENCES Easton DF et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016 May;53(5):298-309. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212315 SCV000887984 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing
Color RCV000116130 SCV000902711 likely benign Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing

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