ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1441G>T (p.Gly481Cys) (rs587780229)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220981 SCV000277341 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Color RCV000220981 SCV000912107 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000116126 SCV000150035 uncertain significance not provided 2014-02-20 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1441G>T at the cDNA level, p.Gly481Cys (G481C) at the protein level, and results in the change of a Glycine to a Cysteine (GGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Gly481Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a neutral non-polar amino acid is replaced with a neutral polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on the currently available information, we consider BRIP1 Gly481Cys to be a variant of uncertain significance Furthermore, BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood.
Invitae RCV000530704 SCV000633556 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 481 of the BRIP1 protein (p.Gly481Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with breast cancer or  pancreatic cancer (PMID: 25452441, 28767289). ClinVar contains an entry for this variant (Variation ID: 128158). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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