ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1871C>A (p.Ser624Ter) (rs587781321)

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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 RCV000129060 SCV000183760 pathogenic Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000254651 SCV000210847 pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1871C>A at the cDNA level and p.Ser624Ter (S624X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Ser624Ter, also reported as S624*, was observed in multiple individuals with ovarian or breast cancer and/or a family history of ovarian or breast cancer (Kanchi 2014, Lu 2015, Ramus 2015, Thompson 2016). This variant is considered pathogenic.
Invitae RCV000228701 SCV000290992 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser624*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587781321, ExAC 0.001%). This variant has been observed in individuals affected with ovarian cancer (PMID: 26315354, 26720728), and an individual affected with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 140852). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254651 SCV000600895 pathogenic not provided 2017-02-13 criteria provided, single submitter clinical testing
Counsyl RCV000576387 SCV000677799 pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2017-04-05 criteria provided, single submitter clinical testing
Color RCV000129060 SCV000689288 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589135 SCV000699678 pathogenic Hereditary breast and ovarian cancer syndrome 2019-08-09 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1871C>A (p.Ser624X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 255438 control chromosomes (gnomAD). The variant, c.1871C>A, has been reported in the literature in multiple individuals affected with breast- and/or ovarian cancer (Kanchi_2014, LaDuca_2014, Ramus_2015, Thompson_2016, Huang_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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