ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.749C>G (p.Thr250Arg) (rs1555609275)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550168 SCV000633712 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 250 of the BRIP1 protein (p.Thr250Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRIP1-related disease. 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, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000568986 SCV000661493 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV001193529 SCV001362424 uncertain significance not specified 2019-01-14 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.749C>G (p.Thr250Arg) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245912 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.749C>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001252983 SCV001428470 uncertain significance Familial cancer of breast 2019-02-05 criteria provided, single submitter clinical testing

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