ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3290A>C (p.Glu1097Ala) (rs876658746)

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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 RCV000220039 SCV000274407 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000220039 SCV000684255 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590421 SCV000699719 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.3290A>C (p.Glu1097Ala) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 1/131630 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). To our knowledge, the variant has been reported once in the literature, without strong evidence for causality. In addition, one clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000701514 SCV000830317 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1097 of the BRIP1 protein (p.Glu1097Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. 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: 230751). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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