ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3237T>G (p.Ile1079Met) (rs587781666)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129821 SCV000184635 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000200144 SCV000255169 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1079 of the BRIP1 protein (p.Ile1079Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs587781666, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 141336). 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. 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.
Counsyl RCV000662741 SCV000785520 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-09-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758998 SCV000888001 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780068 SCV000917090 uncertain significance not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.3237T>G (p.Ile1079Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 277116 control chromosomes, predominantly at a frequency of 0.00021 within the African subpopulation in the gnomAD database, which does exceed the estimated maximum expected allele frequency for a pathogenic BRIP1 variant by 3-folds. However, 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.3237T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000129821 SCV001339559 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing

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