ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2405A>G (p.Asp802Gly) (rs876660273)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222483 SCV000277565 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV000781184 SCV000919066 uncertain significance not specified 2018-11-05 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2405A>G (p.Asp802Gly) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal 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 244614 control chromosomes (gnomAD). 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.2405A>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 and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000548413 SCV000633609 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 802 of the BRIP1 protein (p.Asp802Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 233229). 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 C0"). 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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