ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2146A>G (p.Asn716Asp) (rs1060501745)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465706 SCV000547278 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-05-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 716 of the BRIP1 protein (p.Asn716Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. 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 output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The aspartic acid amino acid residue is also 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000563216 SCV000666211 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-22 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence
Color RCV000563216 SCV001344507 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193532 SCV001362427 uncertain significance not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2146A>G (p.Asn716Asp) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245990 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.2146A>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.

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