ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.689C>T (p.Ser230Leu) (rs759031349)

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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 RCV000166271 SCV000217052 likely benign Hereditary cancer-predisposing syndrome 2017-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Color RCV000166271 SCV000910947 likely benign Hereditary cancer-predisposing syndrome 2016-10-01 criteria provided, single submitter clinical testing
Counsyl RCV000411446 SCV000490003 uncertain significance Fanconi anemia, complementation group J 2016-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000409005 SCV000490004 uncertain significance Neoplasm of ovary 2016-09-19 criteria provided, single submitter clinical testing
GeneDx RCV000386668 SCV000329151 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.689C>T at the cDNA level, p.Ser230Leu (S230L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been observed in at least one individual with serous ovarian cancer and one individual with endometrial cancer (Ramus 2015, Ring 2016). However, this variant was also observed in a control individual (Easton 2016). BRIP1 Ser230Leu was observed at an allele frequency of 0.073% (25/34,404) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Ser230Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000477008 SCV000558577 likely benign Familial cancer of breast; Fanconi anemia, complementation group J 2017-09-18 criteria provided, single submitter clinical testing
PreventionGenetics RCV000386668 SCV000807156 uncertain significance not provided 2016-12-30 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000515765 SCV000611876 likely benign Familial cancer of breast 2018-03-28 criteria provided, single submitter research The BRIP1 variant designated as NM_032043.2:c.689C>T (p.Ser230Leu) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of 1.1 to 1 (Thompson et al, 2003, PMID:12900794), which gives very weak support for this allele being associated with cancer risk. The genomic position is not evolutionarily conserved. The variant is reported to be present in approximately 1 in 800 individuals with Latin American ancestry (exac.broadinstitute.org), which is considered too common in the population to cause high cancer risk. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 186643). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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