ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1899C>G (p.Ile633Met) (rs28997572)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220030 SCV000274862 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000234693 SCV000290994 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 633 of the BRIP1 protein (p.Ile633Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs28997572, ExAC <0.01%). This variant has been reported in an individuals affected with breast and ovarian cancer, as well as in unaffected control individuals (PMID: 26315354, 26976419, 26921362). ClinVar contains an entry for this variant (Variation ID: 231114). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000220030 SCV000684166 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing
Counsyl RCV000662814 SCV000785650 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-10-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781165 SCV000919044 uncertain significance not specified 2019-04-20 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1899C>G (p.Ile633Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 288552 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1899C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as unaffected controls (Ramus_2016, Tung_2016, Easton_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Mendelics RCV000990013 SCV001140776 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001171799 SCV001334659 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing

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