ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1871C>T (p.Ser624Leu) (rs587781321)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166032 SCV000216792 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000197937 SCV000255151 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 624 of the BRIP1 protein (p.Ser624Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26921362), and an unaffected individual (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 186440). 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, 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.
GeneDx RCV000284654 SCV000329158 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1871C>T at the cDNA level, p.Ser624Leu (S624L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been reported in three individuals with colorectal cancer, one with breast cancer, and one with synovial sarcoma, but also in 1/3,431 unaffected control subjects (Ramus 2015, Ballinger 2016, Easton 2016, Pearlman 2017, Yurgelun 2017, Hampel 2018). BRIP1 Ser624Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Helicase domain III (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Ser624Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410706 SCV000489945 uncertain significance Fanconi anemia, complementation group J 2016-08-17 criteria provided, single submitter clinical testing
Counsyl RCV000411705 SCV000489946 uncertain significance Neoplasm of ovary 2016-08-17 criteria provided, single submitter clinical testing
Color RCV000166032 SCV000684162 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000284654 SCV000807124 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing
Mendelics RCV000410706 SCV000839376 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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